Immunology

Herd Immunity Herd immunity is essentially a simple concept describing the totality of naturally acquired and vaccine-based immunity to a given infectious agent as a proportion of the whole population. From: Handbook of Models for Human Aging, 2006 Related terms: View all Topics Models for the Study of Infection in Populations John R. Williams, in Handbook of Models for Human Aging, 2006 HERD IMMUNITY Herd immunity is essentially a simple concept describing the totality of naturally acquired and vaccine-based immunity to a given infectious agent as a proportion of the whole population. While the individual objective of vaccination is clearly to prevent or reduce the risk of infection for the individual concerned, the public health objective of vaccination is to increase the level of herd immunity to that required for control or elimination of the infection from the population, and in the longer term on a regional or global scale to eradicate the infection altogether. (Note the distinction between elimination where an infectious agent is no longer present in a particular population and eradication in which the agent is eliminated world- or region-wide; the smallpox virus remains, at the time of writing, the only infection for which global eradication has been achieved.) The term herd immunity is occasionally used to describe the level of population immunity that will result in elimination of a specific infection from a population, but here herd immunity for elimination would be more appropriate. This level of herd immunity for elimination is that at which an infection cannot propagate effectively in the population; at this level of immunity there may be some secondary cases or even short chains of infection, but these chains are sooner or later broken and prove insufficient to prevent the infection from dying out. In other words, the effective reproduction number, R, in these circumstances is less than 1.0. Herd immunity is obviously dynamic, as natural or vaccine-based immunity is lost over time through waning of immunological memory or deaths of immune individuals, and newly susceptible individuals arrive through births or migration. Thus to maintain the effectiveness of vaccination programs, vaccine coverage and herd immunity need to be monitored at regular intervals and if necessary a strategy planned, informed by dynamic modeling, of supplementary vaccination programs introduced to boost herd immunity to the necessary level (Nokes and Anderson, 1988). Epidemiology and control of community infections D. Reid, D. Goldberg, in Medical Microbiology (Eighteenth Edition), 2012 Herd immunity Herd immunity is an important element in the balance between the host population and the micro-organism, and represents the degree to which the community is susceptible or not to an infectious disease as a result of members of the population having acquired active immunity from either previous infection or prophylactic immunization (see p. 731). Herd immunity can be measured: 1 Indirectly from the age distribution and incidence pattern of the disease if it is clinically distinct and reasonably common. This is an insensitive and inadequate method for infections that manifest subclinically. 2 Directly from assessments of immunity in defined population groups by antibody surveys (sero-epidemiology) or skin tests; these may show ‘immunity gaps’ and provide an early warning of susceptibility in the population. Although it may be difficult to interpret the data in absolute terms of immunity and susceptibility, the observations can be standardized to reveal trends and differences between various defined population groups in place and time. The decision whether to introduce herd immunity artificially by immunization against a particular disease will depend on several epidemiological principles. • The disease must carry a substantial risk. • The risk of contracting the disease must be considerable. • The vaccine must be effective. • The vaccine must be safe. The effectiveness and safety of immunization programmes are monitored by observing the expected and actual effects of such programmes on disease transmission patterns in the community by appropriate epidemiological techniques. Cervical Cancer: Screening, Vaccination, and Preventive Strategies Paolo Giorgi Rossi, Francesca Carozzi, in Encyclopedia of Cancer (Third Edition), 2019 Vaccination of boys Herd immunity is the main driver for the proposal of universal vaccination, that is, including boys and girls. With growing evidence of the involvement of HPV in a relevant proportion of head and neck cancers, in particular oropharynx (Plummer et al., 2016), it has become clear that the burden of vaccine-preventable disease in males is not negligible (de Martel et al., 2017). The vaccine has proven to be effective also on precancerous lesions of genital mucosae in males (Palefsky et al., 2011). Nevertheless, most models still predict that the largest benefit of vaccinating boys is the indirect effect on cervical cancer in women due to the reduction of circulating virus and to establishing of herd immunity faster (Brisson et al., 2011). The opportunity and cost effectiveness of vaccinating boys is still under debate, with the extreme heterogeneity of policies adopted in industrialized countries reflecting this uncertainty. Given the very high incidence of HPV-related cancers in males having sex with males, there is consensus that vaccinating this group is opportune (Markowitz et al., 2014; Kirby, 2015; Sauvageau and Dufour-Turbis, 2016), even though implementing effective strategies to target high-risk populations without indirectly fostering discrimination or stigmatization is challenging. Influenza vaccine—live Catherine J. Luke, ... Kanta Subbarao, in Vaccines (Sixth Edition), 2013 Herd immunity and indirect protection from LAIV Herd immunity is defined as the proportion of persons with immunity in a given population,180 and the indirect protection afforded by this immunity to the unimmunized segment of the population is defined as the herd effect. Herd immunity has been demonstrated for infectious diseases of viral and bacterial etiology, and it is widely accepted that this phenomenon occurs with influenza.181 Despite the facts that influenza vaccine policy in the United States has been focused on the immunization of persons aged 65 years and older and that vaccination rates increased from 31% to 67% between 1989 and 1997, influenza epidemics still cause widespread morbidity and mortality in this age group.181–183 Several lines of evidence suggest that widespread immunization of otherwise healthy populations may result in interruption of transmission of influenza and thereby may indirectly protect those in high-risk groups. For example, vaccination of health care workers was associated with reduced morbidity and mortality from influenza among nursing home residents,184–188 and health care workers now constitute a priority group for influenza vaccination in the United States.169 Widespread vaccination of schoolchildren has also been proposed as a measure to reduce the burden of influenza in the community, because children are important vectors for the spread of influenza. The ability to modify the course of an influenza outbreak by vaccination of schoolchildren has been demonstrated in several studies. A vaccination rate of 86% in schoolchildren in Tecumseh, Michigan, with a monovalent inactivated vaccine, resulted in a three-fold reduction in the excess attack rate for the community from influenza compared with a neighboring community in which schoolchildren were not vaccinated.189 A clear difference was observed in the rates of school absenteeism between the communities, and there was evidence that protection was not limited to children of school age. In Japan, vaccination of schoolchildren was mandatory between 1977 and 1987. In 1987, the laws were relaxed, and parents could decide whether or not their children received vaccine. In 1994, vaccination rates fell to low levels amid doubts about the effectiveness of the program. In an analysis of all-cause mortality and death attributed to influenza and of vaccination rates from Japan and from the United States between 1949 and 1998, Reichert and colleagues found that excess mortality rates, predominantly in older persons, dropped significantly in Japan with initiation of the vaccination program for schoolchildren, from rates 3 to 4 times those in the United States to rates similar to the United States.190 Excess mortality rates in Japan increased with discontinuation of the vaccination program for schoolchildren. From a practical standpoint, LAIV could be an extremely effective method to achieve herd immunity if high vaccination rates with an efficacious vaccine are achieved in schoolchildren and influenza transmission to other segments of the community is interrupted. Large numbers of children could be vaccinated in a short period of time, and intranasal administration is preferred over injection of inactivated vaccine. There is evidence from several studies that this is an effective approach. A study conducted in the 1990s demonstrated that vaccination of schoolchildren with either inactivated or Russian LAIV resulted in significant protection. In schools where the children received LAIV, vaccination rates and illness among staff and unvaccinated children were inversely correlated, suggesting reduction of transmission as a result of vaccination. Such a correlation was not seen in the schools where children received inactivated vaccine or in schools where children received placebo.191 There are several studies in a community in central Texas that report both direct and indirect protection against ILI afforded by vaccination of children. In these studies, age-specific rates of MAARI during the influenza season in intervention communities, where children received LAIV, were compared with rates in comparison communities, where children did not receive vaccine. Vaccination of approximately 20% to 25% of children, 1.5 to 18 years of age, in intervention communities resulted in indirect protection of 8% to 18% against MAARI in adults older than 35 years. This small effect may translate into a substantial effect at the population level. Moreover, the size of this effect may be diluted from use of clinical rather than laboratory endpoints.192 In another study, significant protection against laboratory-confirmed influenza illness and pneumonia and influenza events was observed in the children who received LAIV, but not in those who received TIV. Indirect effectiveness against MAARI was observed in 5- to 11-year-old children and in 35- to 44-year-old adults.193 In a third study,194 when schoolchildren were vaccinated with LAIV against antigenically mismatched influenza viruses, significant indirect protection from influenza was observed in all age groups, with the exception of those aged 12 to 17 years. Combined virologic surveillance and MAARI visit data suggested that a single dose of LAIV provided better protection against influenza than TIV. King and colleagues reported a small pilot study followed by a larger, multistate, school-based immunization intervention study using LAIV.195,196 In the pilot study,195 significant (45% to 70%) relative reductions in fever or respiratory illness–related outcomes including physician visits by adults, physician visits by children, prescription or other medicines purchased by household members, and family schooldays and workdays missed, were observed for intervention ("target") school households compared with control school households. In the larger trial, intervention school households reported significantly fewer ILI-related doctor or clinic visits for children; fewer episodes of fever plus cough or sore throat in children and adults; lower ILI-related prescription, over-the-counter, and herbal medication use for ILI; lower absenteeism rates for elementary and high-school students; and fewer missed workdays for adults caring for their own ILI or for others during the peak influenza week. Relative reductions across these outcomes ranged from 25% to 40%, again confirming indirect as well as direct benefit. Limitations of this study included the lack of placebo groups and the use of questionnaires for reporting of ILI. In summary, a large body of data demonstrates the effectiveness of vaccination of schoolchildren for the control of influenza in communities, from both direct and indirect effects of immunization. Both LAIV and TIV are highly efficacious against influenza in children, and a mechanism to explain how LAIV could afford better indirect protection is not clear. The data from these studies support the widespread vaccination of schoolchildren as a means of reducing morbidity and mortality in other high-risk members of communities. Vaccine-Preventable Diseases In Immunology for Pharmacy, 2012 Summary • Herd immunity forms the theoretical basis for mass vaccination programs. • In the twentieth century, mass vaccination programs were highly successful in eradicating childhood diseases such as diphtheria, pertussis, and tetanus. • Vaccines administered by the subcutaneous or intramuscular route prevent dissemination of bacteria or viruses to multiple organs but may not prevent infection. • Vaccines that are administered by the intranasal route prevent both infection and dissemination of bacteria or viruses. • Bacterial antigens used in vaccines are usually stable. • Viral antigens often change as a consequence of antigenic drift, antigenic shift, or genetic reassortment. Community Protection Paul E.M. Fine, ... W. John Edmunds, in Plotkin's Vaccines (Seventh Edition), 2018 Case Reproduction Numbers We can approach this herd immunity concept from an alternative, and equally informative, perspective. If an infection is to persist, each infected individual must, on average, transmit the agent to at least one other individual. If not, incidence will decline and the infection will disappear progressively from the population. The number, or distribution, of actual onward transmissions per case thus describes the spread of an infection in a population, and it is a function of four things: (1) the duration of infectiousness; (2) the likelihood of transmission per “contact” between infectious and susceptible individuals; (3) the rate and pattern of contact between members of the host population; and (4) the proportion susceptible in the host population. Its value under any set of circumstances is known as the reproduction number of the infection, by analogy with standard demographic measures (the average number of progeny per individual per generation). This average number of actual transmissions should be at a maximum if all members of the host population are susceptible—in which circumstance it is known as a basic reproduction number (R0), defined formally as the average number of transmissions expected from a single primary case introduced into a totally susceptible population.14,15 This definition can be translated directly into the mass action formulation (Eq. 1) by setting Ct = 1 and St = T, to represent the single case introduced into a fully susceptible population. The number of secondary cases, Ct + 1, is then equivalent, by definition, to the basic reproduction number (R0): [Eq. 4]Ct+1=T×r=R0 This basic reproduction number describes the maximal spreading potential of an infection in a population. Continuing with the example in Fig. 77.3, the introduction of a single primary case into the population of T = 100,000 susceptible persons should lead to 10 secondary cases (Ct+1=100,000 × 0.0001 = 10 = R0). Table 77.2 shows examples of numerical values of this statistic that are applicable to different infections and derived by methods described later. Fig. 77.5A is an illustration of the concept. If immune individuals are present in a population, then some of the contacts of infectious individuals will be with these immune persons, and hence will fail to lead to transmission. As a result, the average number of actual infection transmissions per case will be less than the basic case reproduction number, and this has been defined as the net, or actual, or effective, reproduction number (Rn).13,14 The actual number of transmissions (Rn) should be equivalent to the basic case reproduction number (R0) times the proportion susceptible in the population (S): [Eq. 5]Rn=R0×S By this expression, if the proportion susceptible (S) were equal to the reciprocal of the basic reproduction number of the infection (1/R0), the average number of transmissions per case (Rn) should be 1, and thus incidence should remain constant over time. Fig. 77.5B illustrates this, and it once again leads us directly to the herd immunity threshold (H). Because the proportion immune is just the complement of the proportion susceptible (H = 1 − S), we have [Eq. 6]H=1−1/R0=(R0−1)/R0 The same expression can also be derived just by combining Eqs. 3 and 4. As long as the proportion immune is maintained above this threshold, incidence should decrease, ultimately to the point of eradication of the infection from the population. Fig. 77.6 shows the relationship graphically, which shows the implications for persistence or decline of an infection depending on its basic reproduction number and the proportion of immune persons in the population.1,13,16 Poliovirus vaccine—inactivated Emmanuel Vidor, Stanley A. Plotkin, in Vaccines (Sixth Edition), 2013 Herd immunity The best evidence for a herd immunity effect of IPV is the experience in the United States where IPV was introduced into routine use in 1955 and was replaced by OPV in 1962. A sharp drop in the numbers of cases of paralytic and nonparalytic polio was evident during the years 1955 to 1962 (Figure 27-5). The apparent reduction in the number of cases observed exceeded the expectation based on the percentage of children vaccinated (Figure 27-6).214 More specific regional data were published that suggested a greater than expected reduction in polio cases.215 The second example of herd immunity comes from the Netherlands where vaccination is refused by a religious community that is well dispersed throughout the country, although IPV is routinely administered to the rest of the population. Two outbreaks of polio have occurred in this religious group, one caused by type 1 virus in 1978 (110 cases) and the second by type 3 virus from 1992 to 1993 (71 cases). Despite the wide circulation of the virus in this community, there was only one case of polio in other Dutch communities. Approximately 400,000 unvaccinated individuals not belonging to this religious community also remained unaffected.216–220,270 The virulent viruses also spread to similar religious groups in North America, but cases only resulted from the 1978 outbreak.221–223 Oostvogel et al224 did an analysis of the circulating viruses in schools affected by the outbreak from 1992 to 1993. Proof of recent type 3 infection was found in 59.5% of the unvaccinated children and in 22.2% of the vaccinated children. The evidence for herd immunity comes from countries where oral-to-oral transmission was probably the dominant mode of interhuman poliovirus transmission. It is less clear if IPV is able to induce herd immunity in countries where the fecal-to-oral route is thought to be the primary role in transmission. Rabies Control in Wild Carnivores RICHARD C. ROSATTE, ... DAVID H. JOHNSTON, in Rabies (Second Edition), 2007 10.2 Bait density Control ultimately depends on establishing herd immunity through animals taking baits and sero-converting. Hence, bait density must correlate with animal density in some positive fashion (Rosatte and Lawson, 2001). This includes the density of all bait-consuming species, not just the target vector. Non-target species, such as opossum (Didelphis virginiana), may consume a considerable proportion of baits intended for raccoons. In urban habitats, raccoon density may be extremely high, e.g. in Washington DC raccoon density was 67–333/km2 (Riley et al., 1998). High bait densities will be required to reach a substantial portion of the population. In Scarborough, Ontario, where raccoon density ranged from 37 to 94/km2 (Broadfoot et al., 2001), raccoon acceptance of baits was 74% when bait density was 200/km2 (Rosatte and Lawson, 2001). Roscoe et al. (1998) used fishmeal polymer V-RG baits at a density 64/km2 in the Cape May area of New Jersey to control raccoon rabies during 1992–1994. Tetracycline was detected in 73% of the sampled raccoons and 61% of the raccoons tested seroconverted (Roscoe et al., 1998). In Newfoundland, under severe winter snowconditions, Whitney et al. (2005) eradicated an invading epizootic of arctic-strain rabies in red fox using a density of 35 baits/km2 and, in France, Vuillaume et al. (1998) distributed vaccine baits at fox dens at a density of 11.4 baits/den. Given the wide variation in results in a small number of trials, it is necessary in planning ORVPs to consider other factors, such as the methods of vaccine placement, timing of vaccination, spatial variations in animal density and bait design (Table 18.1) (Bachmann et al., 1990; Robbins et al., 1998; Olson et al., 2000; Rupprecht et al., 2004). TABLE 18.1. Baiting success guidelines derived from counts of tetracycline biomarker lines in teeth of carnivore vector species Species (location)a Sample (n) (year class) Total tetracycline biomarker (%+) Median (range), tetracycline biomarker lines/(+) animal Baiting success, guideline (Type) Red fox (NL)b 25 (1st year class) 66 6.3 (1–11) BSG, Type 1 Coyote (TX)c 117 (1st year) 82 3.3(1–8) BSG, Type 1 Red fox (ON)d 210 (all years) 70 2.8 (1–28) BSG, Type 2 Red fox (DE-Rügen)e 28 (all years) 75 2.5 (1–7) BSG, Type 2 Red fox (CZ)f 19 210 (all years) 78 2.0 BSG, Type 2 Raccoon (NY)g 207 (all years) 73 2.0 (1–9) BSG, Type 2 Raccoon (OH)h 22 (1st year) 76 1.5(1–6) BSG, Type 2 Gray fox (TX)c 141 (1st year) 36 2.1 (1–5) BSG, Type 3 a NL = Newfoundland, TX = Texas, ON = Ontario, DE = Deutschland, CZ = Czech Republic, OH = Ohio; b Whitney et al. (2005); c Sidwa et al. (2005); d Johnston and Voigt (1982); e Müller et al. (unpublished); f Matouch and Vitasek (2005); g Bigler and Lein (2001); h Nohrenberg, USDA(unpublished). Neisseria meningitidis David S. Stephens, Michael A. Apicella, in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015 Herd Immunity and Introduction Strategies Protection against the bacterial meningitis pathogens through herd immunity is a remarkable, powerful, and unanticipated effect of bacterial polysaccharide-protein conjugate vaccines.35 Herd immunity can account for approximately one half of their effectiveness at preventing disease and has significantly enhanced their cost-effectiveness. It is an important strategy for vaccine introduction, implementation, and evaluation. As noted, in 1999 to 2000 the meningococcal serogroup C conjugate vaccines were introduced in the United Kingdom as a broad catch-up campaign for those younger than 19 years of age, reduced nasopharyngeal carriage of serogroup C in adolescents more than 75%, and created herd immunity that has persisted for more than a decade.413,417 The explanation for this remarkable herd immunity effect is the low R0 (basic reproduction number, or the average number of secondary infectious cases that are produced by a single index case in completely susceptible population), estimated at 1.3, for meningococcal disease providing herd immunity with 17% to 26% vaccine coverage of the population.35,434 In contrast, measles, mumps, pertussis, polio, and rubella have an R0 greater than 5 and require much higher thresholds (i.e., >80% for herd immunity).427 The immunologic basis of mucosal (herd) immunity with conjugate vaccines remains unclear. Generation of capsule-specific mucosal immunoglobulins, transudation of high-avidity serum IgG to mucosal surfaces, and Th17-induced immunity via macrophage clearance have been proposed.35 Cost-effectiveness, measured as a quality-adjusted life-year (QALY) score, is increasingly becoming an important consideration of vaccine recommendations in public health.419 Using standard cost-effectiveness methods, a recent analysis estimated a routine infant meningococcal vaccination program was approximately $647,000 per QALY saved compared with the $157,000 per QALY saved with the two-dose adolescent vaccination program at the current price of $90 a dose. The ACIP concluded that routine infant meningococcal vaccination with HibMenCY was not cost-effective at this time.433

Viewpoint Free access | 10.1172/JCI151092 Is complement the culprit behind COVID-19 vaccine-related adverse reactions? Dimitrios C. Mastellos,1 Panagiotis Skendros,2 and John D. Lambris3 Published May 4, 2021 - More info View PDF Rare thrombotic reactions to adenovirus-based COVID-19 vaccines Undeniably, a global and coordinated COVID-19 vaccination effort is a prerequisite for taming the spread of emerging SARS-CoV-2 variants and achieving population-wide immunity that can thwart future viral surges. Ongoing vaccination programs have relied on both mRNA and adenoviral-based formulations eliciting potent humoral responses and showing safety in the majority of the population vaccinated so far. However, rare vaccine-related adverse events were recently reported in individuals who received the adenoviral-encoded ChAdOx1 nCov-19 and Ad26.COV2.S vaccines (1–3). Most of these cases developed acute thrombotic complications (cerebral venous thrombosis or disseminated intravascular coagulation) and severe thrombocytopenia following the first dose of the vaccine, without any prior history of heparin exposure or known risk factors for thrombophilia. This rare syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), clinically resembles the hallmarks of autoimmune heparin-induced thrombocytopenia (autoimmune HIT) and is linked to the consistent presence of circulating autoantibodies against platelet factor 4 (PF4), which can directly activate platelets in the absence of heparin (2). The prothrombotic action of anti-PF4 antibodies likely involves antibody-mediated platelet activation through IgG-FcγR interactions and similar FcR-mediated engagement of immune effector cells such as monocytes/macrophages and neutrophils (Figure 1). Since VITT is a newly described syndrome, its clinical management mostly relies on its similarities with HIT and non–heparin-dependent autoimmune thrombotic thrombocytopenias. While nonheparin anticoagulants and intravenous immunoglobulin (IVIg) have been proposed as first-line treatments for patients with VITT, these approaches are not fail-safe and entail drawbacks that may curtail their effectiveness (e.g., risk of promiscuous FcR activation, acute anaphylaxis, or even thromboembolic events in the case of intravenous immunoglobulin) (4). Several second-line therapies for HIT have also been suggested, including plasmapheresis, especially when nonheparin anticoagulation is contraindicated because of major bleeding events (5). Thus, more insight into the precise pathophysiology of VITT is needed to enable more personalized medicine approaches. Figure 1 A schematic diagram of the plausible mechanisms by which complement may contribute to the VITT-associated prothrombotic response. Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described in individuals presenting with high titers of platelet-activating anti–platelet factor 4 (PF4) autoantibodies. These antibodies recognize large multiantigenic complexes comprising PF4 and polyanionic structures similar to heparin, and resemble autoimmune heparin-induced thrombocytopenia (HIT). Complement activation can be triggered in multiple ways in patients presenting with VITT and anti-PF4 antibodies. First, the formation of complexes between PF4 and certain vaccine constituents (e.g., adenoviral capsid proteins or DNA) (23) may serve as a scaffold for C3 activation, similarly to what has been observed with PF4-heparin ultra-large complexes. In addition, complement activation can be triggered by the binding of C1q to the anti-PF4 immune complexes that are deposited on the endothelium, monocyte, or platelet surface via binding to polyanionic structures such as glycosaminoglycans (GAGs). Classical pathway activation leads to C3 cleavage, amplification of complement responses via the alternative pathway, downstream generation of proinflammatory C3a and C5a anaphylatoxins, and the formation of the C5b-9 complex. Complement activation fragments mediate a broad range of thromboinflammatory reactions by interacting with complement receptors on platelets, monocytes, and neutrophils. These interactions can induce or enhance FcR-mediated platelet activation, neutrophil-platelet aggregation, and release of TF-loaded neutrophil extracellular traps (NETs) from activated neutrophils. All these processes are fueled by complement activation and can collectively contribute to a prothrombotic environment that may lead to VITT. Moreover, C3-opsonized immune complexes can enhance FcγR-dependent effector responses on platelets further promoting thrombotic responses. Abbreviations: CP, classical pathway; AP, alternative pathway; TF, tissue factor. A proposed role for complement Complement is a host innate immune sentinel comprising over 50 proteins that can be swiftly activated through any of three initiating pathways (classical, lectin, or alternative) that sense microbial invaders or other inflammatory cues, such as immune complexes. In fact, complement activation has been implicated as a perpetrator of immune complex–driven thromboinflammation in autoimmune pathologies such as the antiphospholipid syndrome, a systemic disorder that increases risk for blood clots (6). Prompted by the striking findings in patients who developed VITT after a single dose of adenoviral-associated vaccine, we posit here that the observed thrombotic complications may partly reflect immune complex–triggered complement activation through the classical pathway. PF4-containing immune complexes can be recognized by C1q, a soluble pattern recognition molecule of the classical pathway that binds to the Fc portion of IgG molecules. Anti-PF4 complex–driven classical pathway activation can lead to C3 activation, alternative pathway–mediated amplification of complement responses, and downstream generation of potent proinflammatory mediators and effectors (C3a, C5a and membrane attack complex) that can potentiate thromboinflammation (7). In fact, the thrombogenic capacity of distinct complement activation fragments has been linked to a broad spectrum of immune-related mechanisms that underpin the immunothrombosis of severe COVID-19 (7, 8). Considering that certain allelic combinations of complement gene polymorphisms within the population confer differential susceptibility to deregulated complement activity, it is tempting to speculate that these vaccinated individuals may represent cases where complement deregulation occurs due to genetic alterations that result in ineffective host regulatory control (9). Deregulated complement responses can perpetuate a vicious cycle of inflammatory tissue damage that renders the vascular endothelium and platelet/monocyte compartment more thrombogenic. In this regard, circulating anti-PF4 immune complexes may well serve as a first hit that ignites complement activation, in a way similar to complement-mediated thrombotic microangiopathies (10). The fact that a fraction of these anti-PF4 autoantibodies may recognize antigenic complexes between PF4 and polyanionic structures (such as GAGs or heparan sulfate) raises the possibility that these immune complexes may skew the binding of endogenous complement regulators to host polyanionic surfaces, thereby altering the capacity of these surfaces to withstand autologous complement attack. C3 activation may play a pivotal pathogenic role in this vaccine-induced immunothrombotic phenotype. C3-opsonized anti-PF4 immune complexes can enhance the phagocytic and inflammatory properties of monocytes and neutrophils through the synergistic engagement of FcγR and complement receptors, thereby increasing the thrombogenic milieu in the vasculature (Figure 1). C3 fragment deposition on the endothelium and on platelets/neutrophils can potentiate thromboinflammatory responses by promoting CR3-dependent platelet-neutrophil interactions that favor platelet adhesion and clotting (11). Also, C3aR signaling on platelets can further drive thrombotic responses (12). Of note, it has been shown that PF4–heparin complexes, a hallmark of HIT pathology, can potently activate C3 in the fluid phase and C3 inhibitors such as Cp40 can abrogate C3 activation triggered by HIT-associated PF4–heparin complexes (13). In line with this, the Cp40-based drug candidate AMY-101 has been shown to effectively decrease both neutrophils and neutrophil extracellular trap (NET) formation, two major drivers of HIT-associated thrombosis, in patients with COVID-19 (7, 14–16). Potential treatment approaches In an analogy to HIT, clinical-stage complement C3 inhibitors may represent a novel therapeutic strategy for ameliorating the thrombotic complications elicited in VITT. On one hand, C3 inhibition may quench anti-PF4 antibody production by reducing antigen uptake or processing in the lymphoid tissue. On the other hand, it can broadly suppress multiple paths of immune complex–driven thromboinflammation in VITT (Figure 1). Moreover, C3 inhibition may offer broader therapeutic control of thromboembolic reactions mediated by pathogenic autoantibodies. In this regard, C3 activation, but not C5, was shown to be indispensable for antiphospholipid antibody-induced tissue factor (TF) activation and thrombosis in antiphospholipid syndrome (17). The recently reported resolution of vaccine-induced thrombotic microangiopathy in two patients following combined treatment with anticoagulants and the C5 inhibitor eculizumab further corroborates our hypothesis that therapeutic complement modulation may offer significant clinical benefits to patients with VITT (18). In this regard, C3 inhibitors may exert a broader therapeutic effect than anti-C5 agents by suppressing both terminal pathway activation and thrombogenic pathways operating upstream of C5 (14, 19). Because this newly described immune syndrome is still poorly defined, it would be of great benefit to patients with VITT if the algorithm for VITT clinical management considered diagnostic monitoring of complement biomarkers as a means of validating the use of specific complement inhibitors. As a cautionary note, we should stress that plasma levels of complement proteins reflect both turnover and synthesis. Therefore, the accurate monitoring of complement activity should rely on markers of ongoing activation combined with corroborative functional assays that gauge the impact of complement activation on the tissue or cellular level. mRNA vaccine reactions In addition to these cases of VITT in individuals receiving adenovirus vectored vaccines, the rollout of COVID-19 mRNA vaccines has brought to the spotlight rare adverse events involving a maladaptive immune reaction to certain vaccine constituents. Rare cases of severe allergic reactions (anaphylaxis) were reported following the first dose of the Pfizer–BioNTech or Moderna SARS-CoV-2 mRNA vaccines (20). Such allergic reactions are likely triggered by the PEG or lipid moieties of these mRNA vaccines. They involve complement and mast cell activation in an IgE-independent manner and closely resemble the complement mediated pseudo-allergy reaction (CARPA) that has been described in the case of liposomal carriers (21). Complement activation in this case may be initiated by IgG or IgM directed against the PEGylated lipids of these vaccine formulations. Concluding remarks Taken together, these paradigms of vaccine-related adverse reactions highlight the potential contribution of complement activation to vaccine-related pathology, raise the importance of incorporating complement diagnostic monitoring in the early clinical management of such patients, and endorse complement inhibitors as potential treatment options. In addition to the complement-activating capacity of anti-PF4 antibodies, we cannot rule out the possibility that complement activation in VITT may also be fueled by preformed (natural IgM) or induced IgG antibodies against adenoviral capsid antigens or direct interaction of pattern recognition molecules with capsid elements (22). The relevance of these plausible mechanisms to VITT pathology warrants further investigation. Footnotes Conflict of interest: JDL is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for therapeutic purposes. He is the inventor on patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals: US patents 8946145/9371365 (Modified compstatin with peptide backbone and C-terminal modifications), 9630992 (Compstatin analogs with improved pharmacokinetic properties), 9579360 (Methods of treating or preventing periodontitis and diseases associated with periodontitis). JDL is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals, i.e., 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan/empaveli and APL-9: US patents 6319897 (Peptides which inhibit complement activation), 7989589 (Compstatin analogs with improved activity), 7888323 (Potent compstatin analogs). Copyright: © 2021, American Society for Clinical Investigation. Reference information: J Clin Invest. 2021;131(11):e151092. https://doi.org/10.1172/JCI151092. References Muir K-L, et al. 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View this article via: JCI PubMed CrossRef Google Scholar Hamad OA, et al. Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18. Thromb Haemost. 2015;114(6):1207–1217. View this article via: PubMed Google Scholar Sauter RJ, et al. Functional relevance of the anaphylatoxin receptor C3aR for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis. Circulation. 2018;138(16):1720–1735. View this article via: PubMed CrossRef Google Scholar Khandelwal S, et al. Novel immunoassay for complement activation by PF4/heparin complexes. Thromb Haemost. 2018;118(8):1484–1487. View this article via: PubMed CrossRef Google Scholar Mastellos DC, et al. Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clin Immunol. 2020;220:108598. View this article via: PubMed Google Scholar Gollomp K, et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight. 2018;3(18):99445. View this article via: JCI Insight PubMed Google Scholar Perdomo J, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10(1):1322. View this article via: PubMed CrossRef Google Scholar Müller-Calleja N, et al. Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies. Blood Adv. 2018;2(9):979–986. View this article via: PubMed CrossRef Google Scholar Tiede A, et al. Prothrombotic immune thrombocytopenia after COVID-19 vaccine. [published online April 30, 2021]. Blood. https://doi.org/10.1182/blood.2021011958. View this article via: PubMed Google Scholar Hillmen P, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028–1037. View this article via: PubMed CrossRef Google Scholar Castells MC, Phillips EJ. Maintaining safety with SARS-CoV-2 vaccines. N Engl J Med. 2021;384(7):643–649. View this article via: PubMed CrossRef Google Scholar Klimek L, et al. Allergenic components of the mRNA-1273 vaccine for COVID-19: possible involvement of polyethylene glycol and IgG-mediated complement activation. [published online March 3, 2021]. Allergy. https://doi.org/10.1111/all.14794. View this article via: PubMed Google Scholar Chéneau C, Kremer EJ. Adenovirus-extracellular protein interactions and their impact on innate immune responses by human mononuclear phagocytes. Viruses. 2020;12(12):1351. View this article via: PubMed CrossRef Google Scholar Greinacher A, et al. Towards understanding ChAdOx1 nCov-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) [preprint]. https://doi.org/10.21203/rs.3.rs-440461/v1 Posted on Research Square April 20, 2021. Version history Version 1 (May 4, 2021): In-Press Preview Version 2 (June 1, 2021): Electronic publication

Summary Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune‐interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat‐associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses. 1 FIBROBLASTIC RETICULAR CELLS UNDERPIN THE STRUCTURE OF LYMPHOID ORGANS The activation of adaptive immune responses depends on the interaction of professional antigen‐presenting cells (APC) with T and B cells in specialized compartments of lymphoid organs. Secondary lymphoid organs (SLO) are strategically positioned at routes of pathogen invasion and thereby increase the likelihood of lymphocytes to encounter their cognate antigens at a particular location and during a certain time window. Lymph nodes are found at convergence points of afferent lymph vessels and surveil extracellular fluids from separate areas of peripheral tissue. Other classical SLO such as Peyer′s patches are located right below the area of the intestinal surface they surveil, while the splenic white pulp provides specialized niches for the development of immune responses against blood‐borne pathogens.1 Nonclassical SLO such as fat‐associated lymphoid clusters (FALC) serve as surveillance hubs of the body cavities by sampling the fluids that are secreted by mesothelial cells.2 Transient lymphoid aggregates that display T‐ and B‐cell zone segregation and that appear in inflamed tissues are referred to as tertiary lymphoid structures (TLS, also known as tertiary lymphoid organs).3 Fluid flow in lymphoid organs is sustained by endothelial stromal cells with blood endothelial cells facilitating the delivery of oxygen and nutrients via blood vessels and lymphatic endothelial cells granting drainage of extracellular liquids via lymphatic vessels. The structural integrity of all lymphoid organs is determined by fibroblastic stromal cells that build, for example, the capsule of lymph nodes or the spleen. In addition, specialized immune‐interacting fibroblasts, generally termed fibroblastic reticular cells (FRC), form the scaffold structures that underpin the distinct microenvironments required for efficient immune cell interactions (Figure 1). FRC crucially contribute to the functioning of the immune system through the secretion of homeostatic chemokines to coordinate the interaction between APC and lymphocytes and provide growth and survival factors that nurture both innate and adaptive lymphocytes.4, 5 Moreover, FRC are equipped with a large range of pattern recognition receptors6-8 that play a crucial role in the control innate immune reactions. The detection of pathogen‐associated molecular signatures by germline‐encoded receptors is a key determinant for the immune system to distinguish harmful molecules of foreign origin from inoccuous self‐molecules.9, 10 Sensing of microbial products by pattern recognition receptors expressed by APC such as dendritic cells and macrophages has been considered as a key step for the activation of the adaptive immune system.9, 11 However, recent studies have revealed that FRC in classical and nonclassical SLO actively shape adaptive immune responses through the integration of innate immunological signals.8, 12 In this review, we will highlight the ability of FRC to generate tissue‐specific microenvironmental niches that orchestrate complex immunological processes and discuss recent work that has revealed the role of FRC as an important nexus of innate and adaptive immune responses. 2 DIVERSITY OF FIBROBLASTIC RETICULAR CELLS IN LYMPHOID ORGANS The most commonly used distinction of endothelial and fibroblastic stromal cells of SLO relies on the expression of the endothelial marker CD31 (platelet endothelial cell adhesion molecule‐1, PECAM‐1) and the fibroblast marker podoplanin (PDPN).13 While PDPN expression captures the majority of FRC in lymph nodes, the expression of this marker in the spleen is restricted mainly to FRC in the T‐cell zone.14 Moreover, PDPN is a surface molecule that is expressed by fibroblasts in nonlymphoid tissues and in tumors15 rendering this marker unsuitable to specifically track lymphoid tissue FRC. In contrast, the promoter activity of the FRC signature genes Ccl19 and Cxcl13 is well‐suited to capture the complexity of the immune‐interacting fibroblasts in SLO.16, 17 Indeed, the Ccl19‐Cre model facilitates targeting of FRC in all relevant microenvironments in lymph nodes,16, 18, 19 in Peyer's patches12 and in the white pulp of the spleen.20 Likewise, the Cxcl13‐Cre/tdTomato transgene targets the majority of FRC in all SLO.17 The combination of such advanced transgenic mouse models with single‐cell RNA‐seq‐based analyses of lymph node7, 21 and splenic white pulp22 FRC will enable a series of novel studies to further explore the functional complexity of FRC in lymphoid organs. 2.1 The many shapes of FRC in classical secondary lymphoid organs While the differentiation trajectories of splenic white pulp FRC from perivascular progenitors have been delineated recently using Ccl19 promoter‐based cell fate mapping22 and lineage tracing,20 the origin of lymph node FRC has not yet been fully elucidated. Nevertheless, the aggregation of Ccl19‐Cre+ and Cxcl13‐Cre+ cells in the vicinity of blood vessels of the lymph node anlage16, 17 strongly suggests that lymph node FRC originate from myofibroblastic progenitors in the perivascular space. It appears that these precursor cells are able to generate the various FRC subsets that underpin the major compartments of the lymph node (Figure 1A). The lymph fluid from peripheral tissues that arrives to the lymph node via the afferent lymph vessels is drained through the subcapsular sinus which is lined by lymphatic endothelial cells and, beneath the subcapsular sinus floor, by several layers of marginal reticular cells (MRC).23 These cells can be distinguished from other FRC subsets in lymph nodes by the expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM‐1), receptor activator of nuclear factor kappa‐Β ligand (RANKL, TNFSF11), and CXCL13.23 In the spleen, MRC support immune responsiveness by supporting the capture and delivery of antigens from the marginal zone to B‐cell follicles.24 The expression of RANKL by Ccl19‐Cre+ lymph node MRC has been shown to be critical for the integrity of lymphatic endothelial cells in the subcapsular sinus25 indicating that MRC actively participate in shaping the cellular environment of the lymph node. Likewise, splenic white pulp MRC impact the phenotype of their interacting immune cell partners. For example, Notch 2‐driven differentiation of marginal zone B cells and of Esam+ dendritic cells requires the expression of the Notch ligand Delta‐like (DL)1 in splenic Ccl19‐Cre+ cells,26 while RANK has been shown to maintain myeloid cell populations in the marginal zone to secure initiation of antiviral immune responses.27 As an extension from the MRC layer unfolds the conduit system through the lymph node parenchyma as a fibrillary network formed by FRC.28 Conduits both in lymph nodes and in the splenic white pulp are ensheathed by FRC and consist of a collagen‐rich core that is surrounded by a microfibrillar zone and a basement membrane.29, 30 The conduit system conveys low‐molecular‐weight substances such as chemokines and antigens from the lymph node subcapsular sinus through the T‐cell area toward high endothelial venules.30 A recent report revealed that IgM transiently gains access to the luminal side of the lymph node conduit system to facilitate rapid export of early‐response IgM antibodies out of the lymph node parenchyma.31 In sum, MRC of lymph nodes and the splenic white pulp shape the border region of lymphoid tissues through the dedicated interaction with immune cells and other stromal cells and by maintaining communication channels for rapid distribution of immunologically relevant information. It will be important to fully exploit existing and novel reticular cell targeting approaches (such as the CollagenVI‐Cre model32) to characterize the function of MRC in Peyer's patches. T‐cell zone reticular cells (TRC), ie, the FRC that co‐localize predominantly with T cells and dendritic cells, express PDPN and the signature chemokines CCL19 and CCL21.12-14, 22 It is important to reiterate that PDPN expression in lymph nodes can be found in almost all FRC subsets and that high PDPN expression is associated with maturation into fully immunocompetent FRC,16 while PDPN expression both in Peyer's patches and in the splenic white pulp is mainly found in TRC.12, 22 Both T cells and dendritic cells are in close contact with TRC and move along their projections within the T‐cell area.33 The mobility of dendritic cells is boosted by the ligation of the C‐type lectin‐like receptor 2 (CLEC‐2) with PDPN on TRC.34 Moreover, lymph node TRC are thought to function as the major source of the cytokine IL‐7 to promote T‐cell homeostasis.13 However, since IL‐7 can also be produced by lymphatic endothelial cells within lymph nodes35 and in the afferent lymphatics,36 the specific function of TRC‐derived IL‐7 for T‐cell sustenance and activation remains to be demonstrated. B‐cell follicles harbor distinct FRC subsets that produce CXCL13, the B cell‐attracting chemokine that binds to CXCR5.37 As mentioned above, CXCL13‐expressing MRC extend into the B cell follicle, while the most prominent reticular cell subset that underpins the B‐cell area has been named follicular dendritic cell (FDC).38 Due to their dendritic morphology, FDC have been assumed to be related to conventional dendritic cells, ie, to originate from bone marrow progenitors. Only recently, the progenitor cell of FDC has been revealed as perivascular myofibroblast that is characterized by the expression of platelet‐derived growth factor receptor β (Pdgfrb, CD140b).39 FDC in the B cell follicle can be identified by the expression the complement receptors CD21 and CD35 and can be found both in primary and secondary follicles.40 The main functions of FDC are the retention and presentation of particulate antigen on their surface to B cells using a broad range of FCγ‐receptors (ie, CD16, CD32)41 and the promotion of affinity maturation and somatic hypermutation of B cells in the germinal center reaction.42 FDC and probably other FRC subsets43 in the B‐cell follicle control the survival of B cells via B cell activation factor (BAFF) or transmembrane activator and CAML interactor (TACI).44 It has been suggested that the dark zone of the germinal center harbors a subset of CXCL12‐expressing reticular cells (CRC) that express PDPN and can be lineage‐traced using the Ccl19‐Cre and CD21‐Cre model.18 However, a unique phenotype of CRC could not be revealed using single‐cell RNA‐seq analysis7 indicating that the phenotypical distinction of FRC/FDC subsets underpinning the germinal center is still unclear. A main fraction of FRC express markers that are indicative for their perivascular location such as Itga7 (integrin α7), Pdgfrb (CD140b), and Acta2 (αSMA) in lymph nodes6, 7 and Ly6a (Sca‐1), Pdgfra (CD140a), and Vcam1 (CD106) in the spleen.22 It is likely that the perivascular reticular cell (PRC) fraction harbors the adult progenitor of all FRC subsets.22, 39 Other regions of the lymph node such as the deep cortical area appear to harbor a subset of FRC that is characterized by the expression of CCL21a, CXCL12, and LepR.19 This area of the lymph node is occupied by T cells, dendritic cells, and B cells suggesting that FRC acquire distinct phenotypical properties when they interact with multiple cell types. Indeed, FRC attain yet other properties when they co‐localize in medullary cords with macrophages, NK cells, and plasma cells.19 In this location, medullary reticular cells (medRC) express high levels of CXCL12, IL‐6, and BAFF and facilitate thereby the formation of dedicated niches for plasma cells.45 Single‐cell RNA‐seq analysis has confirmed the existence of at least two FRC subsets that localize in the medullary region indicating that medRC also promote the maintenance of NK cells in this region.7 Clearly, further studies are required to unveil the molecular properties and function of FRC subsets not only in the lymph node B‐cell niches but also in the different microenvironments of classical SLO. 2.2 Limited FRC heterogeneity in nonclassical SLO and TLS While the formation of classical SLO, ie, lymph nodes, splenic white pulp and Peyer's patches, is fully dependent on the presence of the lymphotoxin‐β receptor,46 the generation of nonclassical SLO (eg, FALC) or TLS (eg, inducible bronchus‐associated lymphoid tissue [BALT]) is largely independent of this pathway.2 For example, the formation of FALC requires the activation of stromal cells via the production of inflammatory cytokines such as the tumor necrosis factor (TNF), which are induced through the presence of microbiota in the intestine.47 Interestingly, the highly activated milieu of the intestinal lamina propria does not provide sufficient cytokine‐mediated stimulation to override the dependence of cryptopatch and isolated follicle formation on lymphotoxin‐β receptor signaling,48 indicating that the pathways employed in the generation of nonclassical SLOs are organ‐dependent. Likewise, TLS, which are locally inducible leukocytic aggregates that form in chronically inflamed nonlymphoid tissues,49 can form in different organs in a context‐dependent manner through triggering of inflammatory circuits involving IL‐17, IL‐6, IL‐1β, and/or IL‐22.50-53 In terms of structural organization and FRC content, both nonclassical SLO (Figure 1B) and TLS (Figure 1C) exhibit a reduced complexity when compared to the classical SLO. We will focus our review here on FALC and inducible BALT as examples of nonclassical SLOs and TLS, respectively, to highlight the few knowns and many unknowns of FRC biology in these compartments. FALC are located beneath the mesothelium and are surrounded by adipose tissues. A clear structural segregation of lymphocytes is not recognizable with a dense cluster of B cells being intermingled with CD4+ T cells and CD11b+ myeloid cells.54, 55 The main B cell population within FALC are B1 B cells that patrol body cavities and are the source of natural, low‐affinity immunoglobulin M (IgM) antibodies that bind to pathogenic bacteria.56 FALC also contain innate lymphoid cells (ILC), particularly type 2 ILCs and NKT cells.47, 55 The production of CCL19 and CCL21 by FALC FRC most likely mediates the attraction and retention of naive T cells.54 PDPN‐expressing FRC that underpin FALC structures are highlighted by the Ccl19‐Cre transgene, express PDPN and occupy perivascular niches with a surface marker profile that resembles splenic PRC (ie, PDGFRα+VCAM‐1+ICAM‐1+).8 Although these cells do not display the general phenotype of MRC or FDC, FALC FRC have been shown to produce the B cell‐attractant CXCL13.57 Hence, it appears that the somewhat random mixture of T and B cells in FALC is due to a high versatility of FALC FRC which permits attraction and interaction with B cells, T cells, and myeloid cells. Clearly, FALC FRC—and probably as well the FRC underpinning intestinal isolated lymphoid follicles—can steer both innate and adaptive immune responses without forming distinct microenvironments such as germinal centers. The formation of TLS is frequently associated with chronic inflammatory and autoimmune diseases.3, 58 Importantly, in the context of cancer, the presence of TLS correlates with improved survival in a growing list of human cancers including breast cancer,59 lung cancer,60 oral squamous cell61 and Merkel cell carcinomas,62 and melanoma.63 Hence, it is tempting to speculate that TLS serve as inducible and transient outposts of the immune system to locally cope with ongoing immunological threats. Moreover, it appears that the coordination of immune cell interaction within these structures relies on organizational principles that are comparable to those in the classical SLO (Figure 1C). During tumor formation, TLS undergo a maturation process that has been suggested to start with the segregation of T‐cell and B‐cell areas in the perivascular space and progresses by the appearance of germinal centers.64, 65 The subsequent development of germinal centers in tumor TLS is accompanied by the appearance of CXCL13‐producing, CD21+ FDC networks both in human colorectal cancer65 and in squamous cell carcinoma of the lung.64 The presence of chemokine‐secreting FRC that underpin TLS has been demonstrated in a variety of models of chronic organ inflammation.52, 53, 66 The formation of inducible BALT in the lung has revealed that the activation of the innate immune system via lipopolysaccharide instillation can drive the formation of local TLS in an IL‐17‐dependent fashion,50 while this cytokine is not necessary to induce BALT formation following intranasal infection with a propagation‐deficient virus.67 Nevertheless, viral infection appears to be sufficient to induce highly organized BALT structures that contain B‐cell follicles underpinned by a network of CXCL13‐expressing FDC as well as CXCL12‐producing, yet undefined, reticular stromal cells.66 Furthermore, the bacterial infection with Pseudomonas aeruginosa triggers BALT formation in a TLR‐dependent manner leading to the emergence of CXCL12+ reticular cells that is dependent on γδ T cell‐derived IL‐17, while FDC fail to develop under these conditions.66 Overall, the emerging view is that remodeling and maturation of immune‐stimulating FRC is one of the initiating events in the establishment of an immune‐competent niche capable of recruiting and retaining disease‐relevant lymphocytes in TLS.3 Hence, targeted modulation of FRC differentiation processes within TLS may lead to treatment modalities that either attenuate TLS formation during chronic inflammatory diseases or foster the development of such immune‐activating structures in malignant diseases. 3 IMMUNE CELL‐FRC INTERACTIONS The main function of secondary lymphoid organs is to preempt68 and to deal with1 the encounter of microbial agents and tumor cells. Pathogens and other antigenic material arrive at the antigen‐sampling zone of SLO, eg, the subcapsular sinus region of lymph nodes, where dedicated macrophage/dendritic cell populations take up and transfer antigen to B cells.69, 70 Consequently, disruption of the subcapsular sinus structure results in defective immune responses during secondary infection in mice.71 The cellular infrastructure of the murine splenic marginal zone functions in the same manner and efficiently retains infectious agents.72 Interestingly, it appears that the function of antigen capture and innate immunological sensing in the marginal zone of murine spleens is assigned to CD169‐positive macrophages and/or dendritic cells,69, 72 while in the human spleen MAdCAM1‐positive MRC operate as coordinators of immune cell interaction and drivers of subsequent immune activation.24 Antigens are further dispersed in the lymph node through the lymphatic sinuses that pervade the lymph node parenchyma, and are taken up by distinct dendritic cell subsets for the delivery to CD8+ or CD4+ T cells.73 The interaction of dendritic cells and T cells depends on the infrastructure provided by TRC74 and is regulated by TRC‐derived factors such as CCL2175 or lysophosphatidic acid.76 The efficient interaction of T and B cells at the T‐B border during viral infection depends on the presence of BAFF‐producing FRC.44 Other FRC subsets contribute during the subsequent steps of B‐cell activation in lymph nodes including antigen presentation in the germinal center,42 regulating B‐cell migration during the germinal center reaction,18, 42 and establishing plasma cell competent microenvironments in the medulla.45 FRC can perform these multiple functions because they are able to integrate a variety of signals through sensing of innate immunological stimuli and the differentiation of cellular signals in their immediate environment (Figure 2A). In the following sections, we will summarize how FRC detect and process pathogen‐derived innate immunological signals and illustrate the molecular pathways employed by FRC to regulate adaptive immune responses in lymph nodes, Peyer's patches and FALC. 3.1 Innate immunological sensing by FRC FRC can directly recognize pathogens and their immune‐activating signals using various pattern recognition receptors and particular sets of immune‐activating molecules.6, 7, 77 The activation of in vitro cultivated FRC from SLO12 or FALC8 with various TLR ligands including lipopolysaccharide, poly(I:C), and zymosan leads to upregulation of adhesion molecules ICAM‐1 and VCAM‐1 and the secretion of inflammatory mediators such as CCL2, IL‐6, and TNF. In vivo, lymph node FRC react rapidly to systemic application of lipopolysaccharide with the activation of antigen presentation and type 1 interferon (IFN) pathways and alterations in the generation of extracellular matrix proteins including matrix metalloproteinase‐9, periostin, collagen type VI, and laminin α2.6 Direct ligation of TLR4 on FDC by lipopolysaccharide leads to increased expression of adhesion molecules and promotes the production of antigen‐specific antibodies when FDC are co‐cultured with B cells in vitro.78 Moreover, the activation of FDC by oxidized phospholipids, which function as endogenous TLR4 ligands, can foster the germinal center reaction by promoting higher rates of class‐switch recombination and somatic hypermutation in B cells.79 The formyl peptide receptor 2 that binds microbial products derived from Escherichia coli or Listeria, interacts with the endogenous ligand LL‐37 to enhance CXCL13 and BAFF production by FDC and thereby promotes B‐cell proliferation.80 Viruses can directly infect FRC as demonstrated for the lymphocytic choriomeningitis virus in mice14, 81 and human viruses including Chikungunya virus82 or Ebola virus.83 Complex immune cell interactions are triggered when intracellular viral RNA is recognized by FRC via TLR712 (Figure 2B). The transcriptomic analysis of lymph node FRCs after subcutaneous infection with herpes simplex virus‐1 (HSV‐1) revealed a pronounced activation of type‐I IFN pathway in FRC.77 Virus‐induced inflammation results in FRC proliferation and the induction of a substantial remodeling of the FRC landscape.35, 77 However, excessive activation of TLR7 ligands, eg, through internalization of ribonucleotide proteins complexes via CD21, can result in type 1 IFN production by FDC which supports the long‐lasting maintenance of the germinal center response and sustained production of antinuclear antibodies with perpetuation of a lupus‐like disease in mice.84 Hence, FRC activation through innate immunological pathways requires dedicated control mechanisms to avoid immunopathological sequela. Innate immunological recognition circuits are integrated intracellularly via particular molecular switches such as the myeloid differentiation primary response 88 (MYD88) protein85 and can be amplified by cellular receptors such as the type‐I IFN receptor (IFNAR).86 During infection with the murine cytomegalovirus, blockade of the type‐I IFN pathway leads to a change in viral tropism with a shift from subcapsular macrophages to MRC as the main target cells. The elevated infection rate of MRC leads to the activation and recruitment of NK cells, which efficiently reduce the viral burden in the subcapsular sinus but consequently destroy the reticular cell network of lymph nodes leading to systemic distribution of the virus.87 Overall, it appears that IFNAR signaling in the stromal cell compartment is important to contain viral replication in a broad range of experimental models. However, whether and to which extent IFNAR signaling in FRC directly contributes to the control of a viral infection has not been determined yet. Further FRC innate activation signals can be derived from immune cells that populate their particular microenvironmental niches. For example, in murine FALC, both FRC and hematopoietic cells attracted by FRC can serve as source for TNF8 (Figure 2C). Likewise, human tonsillar FRC respond in vitro to TNF exposure with increased expression of adhesion molecules and enhanced production of inflammatory cytokines.88 Further consequences of innate immunological sensing by FRC include the production of T cell‐activating factors such as IL‐33, which is produced by splenic PDPN+ FRC during vaccination with a recombinant viral vector.89 Single‐cell RNA‐seq analysis has revealed a population of FRC in naive lymph nodes that express high levels of Cxcl9.7 It appears that CXCL9 is mainly provided by stromal cells while CXCL10 is mainly express by murine myeloid cells DC following immunization of mice with dendritic cells that are pulsed with ovalbumin protein and activated with lipopolysaccharide and poly(I:C).90 In sum, FRC actively participate in the earliest phases of developing immune responses through their function as recipients of innate immunological signals and as coordinators of subsequent immune reactions through autocrine and paracrine signal amplification. 3.2 FRC control adaptive immune responses in lymph nodes and Peyer's patches Molecules of the TNF receptor superfamily are not only crucial for the formation of lymphoid organs2, 46, 68, 91 but also profoundly impact the maturation of myofibroblastic progenitors into fully immunocompetent FRC. For example, genetic ablation of lymphotoxin‐β receptor expression on Ccl19‐Cre+ FRC leads to defective FRC maturation with reduced expression of key molecules such as Ccl19, Ccl21, and Il7, that precipitates high susceptibility to viral infection due to impaired activation of T cells.16 While the lymphotoxin‐β receptor appears to affect the maturation of all FRC subsets in lymph nodes, other molecules from the TNF receptor superfamily appear to be required for subset specification. For example, FDC differentiation depends on TNF produced by B cells,92 while CD30 contributes to proper B‐ and T‐cell zone segregation that is associated with reduced PDPN expression on yet undefined FRC subsets.93 The intricate regulatory circuits of FRC‐immune cell interaction that found the basis of protective immune responses is highlighted in a recent study on intestinal Listeria monocytogenes infection in mice.94 Listeria infection induces intestinal epithelial cell proliferation and depletion of goblet cells, while CX3CR1+ myeloid cells in Peyer's patches produce IL‐23 and thereby activate IL‐17‐secreting γδ T cells. The resulting IL‐11 production by PDPN‐expressing cells in Peyer's patches facilitates the activation of enterocytes and limits intestinal villus invasion by Listeria.94 However, such protective FRC‐immune cell interactions may precipitate immunopathological consequences such as a decreased thickness of the mucus barrier that eventually fosters intestinal inflammation.94 Thus, FRC can function both as activating and regulating cellular entities during immune responses. The ability of FRC to negatively impact T‐cell responses has been first noted by the Turley group who demonstrated that FRC in lymph nodes can present peripheral tissue antigens to T cells and thereby attenuate self‐reactivity.95 It has been proposed that the generation of nitric oxide by lymph nodes FRC regulates the expansion and activity of T cells.96, 97 However, since nitric oxide can be produced by other lymph node stromal cells such as lymphatic endothelial cells,96 it remains to be determined, for example, through FRC‐specific ablation of the inducible nitric oxide synthase gene, to which extent FRC regulate T‐cell activity through this mechanism. It is also possible that FRC regulate global immune responsiveness by impacting regulatory T‐cell differentiation. It is generally assumed that dendritic cells are the main cell population that control the differentiation pathway of CD4+ T cells toward the FoxP3+ regulatory T‐cell phenotype.98, 99 However, a recent study suggests that FRC in mesenteric lymph nodes can modulate resident dendritic cells via a bone morphogenic protein‐2‐dependent pathway to foster the induction of regulatory T cells.21 Further studies are warranted to elaborate such direct and indirect pathways of FRC‐dependent immune regulation. Innate lymphoid cells (ILC) regulate immune responsiveness by bridging innate and adaptive immunity. In contrast to T and B cells, ILC lack rearranged antigen receptors and their development and activation is therefore mainly steered via soluble factors and their receptors. Since ILC are particularly abundant at mucosal sites, they are considered as the main cell population that maintains tissue integrity and homeostasis via innate immune mechanisms.100 ILC accumulation at mucosal surfaces relies on the provision of survival factors such as IL‐7 and IL‐15 that can be produced by FRC13, 101 However, ILC also reside in SLO where they are involved in the regulation of adaptive immunity.102, 103 Recently, it has been shown that group 1 ILC are localized in the T cell zones of Peyer's patches and that Ccl19‐Cre+ FRC generate an essential niche for these cells through the provision of IL‐15.12 However, IL‐15 production by PDPN+ FRC in Peyer's patches is rapidly abrogated under excessive inflammatory conditions such as infection with a cytopathic virus. Importantly, the swift cessation of IL‐15 production by FRC in Peyer's patches and mesenteric lymph nodes is dependent on MyD88 signaling which prevents an overshooting activation of NK1.1+ ILC and immunopathological overstimulation of IFN‐γ‐producing Th1 cells (Figure 2B). As a consequence, unrestrained Peyer's patch FRC lacking MyD88 expression permit the rapid clearance of a cytopathic viral infection through boosted ILC1 and Th1 responses which is accompanied by impaired intestinal integrity, bacterial dysbiosis, and chronical intestinal inflammation.12 This study shows that FRC in lymph nodes and Peyer's patches can act as immune rheostats through the regulation of group 1 ILC activity. It will be important to further elaborate the mechanisms that grant FRC in lymphoid organs control over innate and adaptive immune responses. 3.3 FRC‐dependent immune responses in FALC In case of a breach of pathogenic microorganisms into one of the body cavities, protective immunity needs to be mounted swiftly to prevent harm to the internal organs. The adipose tissue underlying the mesothelial surface of the pericardial, pleural and peritoneal cavities harbors variable numbers of FALC.104 In the omentum, a mesothelium‐covered tissue flap that connects stomach, pancreas, colon, and spleen, FALC have been shown to collect fluids and particles from the peritoneal cavity.105 The uptake of inflammation‐inducing substances from the peritoneal cavity such as lipopolysaccharide106 or the lipid‐based antigen zymosan47 induces an increase of omental FALC size and numbers. It has been shown that opsonization of bacterial antigens by natural, low‐affinity IgM antibodies generated by peritoneal B1 B cells can promote the uptake and elimination of bacteria by myeloid cells.107 Moreover, the presence of viral particles in the peritoneal cavity increases the cellularity and size of FALC with concomitant attraction of macrophages from the peritoneal cavity to these structures.108 Other immune cells in the peritoneal cavity such as B‐2 B cells109 or neutrophils110 reach FALC via the blood vasculature. Although FALC lack the compartmentalization observed in classical SLO, their structural foundations support the rapid generation of both T‐ and B‐cell immune responses. For example, intraperitoneal application of antigens such as ovalbumin leads to the initial activation of antigen‐specific CD4+ and CD8+ T cells in omental FALC.54 Similarly, T‐dependent and T‐independent B‐cell responses are generated first in FALC following intraperitoneal antigen application.47 The role of FRC in the initiation of adaptive immune responses in FALC has only recently been clarified. It appears that CXCL13‐expressing FRC in FALC not only support the attraction and retention of B cells,54, 57 but that Ccl19‐Cre+ FALC FRC can directly sense the presence of microbial products via TLR4 and initiate a MyD88‐dependent immune‐amplifying cascade8 (Figure 2C). Following exposure to TLR2 and TLR4 ligands FALC FRC secrete inflammatory cytokines and chemokines including CCL2 to attract CCR2+ inflammatory monocytes from the circulation.8 Inflammatory monocytes establish a crucial crosstalk with FALC FRC that leads to the rapid growth and remodeling of FALC. TNF functions as the main factor that regulates the reciprocal communication between FRC and the myeloid cells and eventually facilitates the generation of humoral immunity within FALC8, 47 (Figure 2C). Interestingly, although FALC lack FDC, the microenvironmental remodeling provided by FRC is sufficient to promote germinal center‐like B‐cell responses with class‐switch recombination and a discrete somatic hypermutation.47, 54 Currently, it remains unknown whether CXCL13+ and CCL19+ FRC represent two distinct cell types or whether a variable expression of the two chemokines represents different functional states. It will be possible to clarify this question by using appropriate cell fate mapping models to track the lineage commitments of FRC subsets within nonclassical SLO. Beyond their prominent function in the initiation and coordination of innate and adaptive immune responses in FALC, FRC present in visceral adipose tissues may also contribute to the maintenance of immune homeostasis and the regulation of the immune‐suppressive environment of adipose tissues under steady‐state conditions. Adipose tissues, including the omental fat favor the accumulation of IL‐10‐producing B cells111 and regulatory T cells.112 Regulatory T cells in adipose tissues are characterized by high expression of the IL‐33 receptor ST2,112 with IL‐33 being one of the main tissue factors that impacts the development and maintenance of regulatory T cells in this compartment.113 Since IL‐33 is mainly produced by FRC‐like cells in FALC,114 it is tempting to speculate that this circuit not only controls B1 B‐cell activation and local IgM production during lung infection and inflammation,114 but that FALC FRC equilibrate immune‐activating and ‐suppressive circuits in these tissues. The regulation of physiological functions by FRC‐derived IL‐33 in the adipose tissue may even extend to other body functions such a thermogenesis.115 Further studies will be required to better understand the molecular processes underlying FRC‐dependent immune activation in FALC. Moreover, it will be important to dissect the relation of FALC FRC to other PDPN expression fibroblasts in visceral adipose tissues and to elaborate the mechanisms employed by FRC that contribute to the maintenance of tissue homeostasis. 4 CONCLUDING REMARKS The translation of innate immune signals into activating or regulating processes that steer adaptive immune responses has been regarded as one of the main roles of professional APC such as dendritic cells. FRC as dedicated immune‐interacting fibroblasts have now entered the stage to be recognized as cells that crucially contribute to the decision‐making within the immune system. The many functions of FRC are accomplished through the generation of specific microenvironmental niches for various types of immune cells. Distinct subsets of FRC form these niches to support immune cell migration, survival, and differentiation. Interestingly, it seems that particular genetic programs are imprinted in the immune‐interacting fibroblasts depending on their anatomical location. The main differentiation switches of FRC differentiation have been identified with the lymphotoxin‐β receptor representing a necessary “signal 1” for FRC maturation in classical SLO.16 However, further research needs to dissect the intercellular communication pathways between FRCs and the various immune cells that impact the differentiation trajectories of FRC in lymphoid and nonlymphoid organs. Indeed, it appears that the intestinal lamina propria of patients suffering from inflammatory bowel disease harbors at least one mesenchymal stromal cell population that closely resembles lymphoid organ FRC and is highlighted by the expression of IL‐33 and Lysyl oxidases.116 Thus, understanding the mechanisms that govern FRC differentiation in SLO and TLS will, for example, open novel avenues to target drugable FRC differentiation pathways in TLS that form during human chronic inflammatory diseases such as rheumatoid arthritis117, 118 or Sjören's syndrome.119 A major challenge that should to be addressed in the future is the lineage relationship of FRC with other mesenchymal cell types such as adipocytes, chondrocytes, or regular tissue fibroblasts. The definition of mesenchymal cell types needs to be coupled to their development origin and their function within a tissue. Hence, a combination of single‐cell transcriptome analysis and faithful in vivo lineage tracing needs to be employed120 to obtain consistent definitions of the cell types that are currently covered by the broad terms “stromal cells” or “mesenchymal cells”. ACKNOWLEDGEMENTS We thank Dr. Natalia Pikor for critical reading of the manuscript. This study received financial support from the Swiss National Science Foundation (grants 166500 and 177208 to BL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES