Immunology

The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester–containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies.

In 2011, a team of Fred Hutch researchers from the Spies Lab in the Clinical Research Division published unexpected findings regarding the stimulatory lymphocyte receptor NKG2D, a well-known mediator of immune surveillance of malignant cells. Signal-triggering molecules that bind to this receptor, NKG2D ligands, are generally not expressed on the surface of normal cells but are induced in most types of cancers, making them a target for cancer-fighting immune cells. The observation that surprised the investigators was that certain cancer cells also express the NKG2D receptor, possibly corrupting this key player into stimulating their own tumor growth (Caballero-Benitez et al. 2011). NKG2D signaling was demonstrated in breast, ovarian, prostate and colon cancer cells, and additional support for the hypothesis was provided through analysis of clinical specimens, positively correlating NKG2D expression with tumor size and spread.

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Key recommendations of the guidelines

Selecting those who should be tested-
The guidelines recommend that:

Systematic testing and treatment of LTBI should be considered for:PLHIV, adult and child contacts of pulmonary TB patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematologic transplantation, and patients with silicosisprisoners, health-care workers, immigrants from high TB burden countries, homeless persons and illicit drug users.Systematic testing for LTBI is not recommended in people with diabetes, people with harmful alcohol use, tobacco smokers, and underweight people provided they are not already included in the above recommendations.Individuals should be asked about symptoms of TB before being tested for LTBI.

Standards for testing and treatment 
 LTBI diagnosis and treatment recommendations in the guidelines are based upon a public health approach with individual benefit, keeping in mind that they complement active TB case finding activities and that individual benefits should outweigh the risk.

The guidelines recommend that either tuberculin skin test (TST) or interferon gamma release assays (IGRA) can be used to test for latent TB.

Consistent with existing WHO recommendations, the guidelines reiterated that IGRAs should not replace TST in low and middle income countries.

The following treatment options  are recommended for the treatment of LTBI in the guidelines:
(i) isoniazid daily for 6 months (6H)
(ii) isoniazid daily for 9 months (9H)
(iii) the combination of rifapentine and isoniazid once a week for 12 weeks (3HP)
(iv) the combination of rifampicin and isoniazid daily for 3-4 months (3-4HR)
(v) rifampicin alone daily for 3-4 months (3-4R)

“Currently, these are the only diagnostic tests available  though they are both weak in predicting future development of TB among infected. Development of better diagnostic tools should be priority for research’ said Dr Alberto Matteelli, Medical officer from the TB/HIV and community engagement unit. 

In addition, the Guidelines Development Panel noted the following critical issues for consideration in the implementation of these guidelines:

Strict clinical observation and close monitoring for the development of active TB disease among contacts of multidrug-resistant TB (MDR-TB) cases, preferably for at least two years over the provision of preventive treatment;Regular clinical monitoring of individuals receiving treatment for latent TB through a monthly visit to the health-care provider;Establishment of national TB drug resistance surveillance systems while implementing national latent TB management services;Introduction of flexible interventions and incentives by national TB programmes that are responsive to the specific needs of population groups at risk, as well as tailored to the local context and their needs to ensure acceptable initiation of, adherence to and completion of LTBI treatment.Documentation of treated individuals through a functional, routine monitoring and evaluation system that is aligned with national patient monitoring and surveillance systems.Creation of conducive policy and programmatic environment, including the promotion of universal health coverage, development of national and local policies, standard operating procedures, as well allocation of dedicated resources.

In the innate immune system, a variety of recognition molecules provide the first-line host defense to prevent infection and maintain endogenous homeostasis. Ficolin is a soluble recognition molecule, which senses pathogen-associated molecular patterns on microbes and aberrant sugar structures on self-cells. It consists of a collagen-like stalk and a globular fibrinogen-like domain, the latter binding to carbohydrates such as N-acetylglucosamine. Ficolins have been widely identified in animals from higher invertebrates to mammals. In mammals, ficolins form complexes with mannose-binding lectin-associated serine proteases (MASPs), and ficolin-MASP complexes trigger complement activation via the lectin pathway. Once activated, complement mediates many immune responses including opsonization, phagocytosis, and cytokine production. Although the precise function of each ficolin is still under investigation, accumulating information suggests that ficolins have a crucial role in host defense by recognizing a variety of microorganisms and interacting with effector proteins.

Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis

Complement is traditionally known to be a system of serum proteins that provide protection against pathogens through direct cell lysis and the mobilization of innate and adaptive immunity. However, recent work indicates that the complement system has additional physiological roles beyond those in host defence. In this Opinion article, they describe the new modes and locations of complement activation that enable it to interact with other cell effector systems, such as growth factor receptors, inflammasomes and metabolic pathways. They propose that the location of complement activation dictates its function.