Killer Cell Immunoglobulin like Receptors (KIR) Gene Variations in Rheumatic Fever

Rheumatic fever (RF) and rheumatic heart disease (RHD) are the post infection autoimmune disease sequelae of pharyngitis caused by Group A streptococcus (GAS) or Streptococcus pyogenes. The annual incidence of GAS infection reaches to 700 million worldwide. A total of 470000 RF cases are diagnosed with 233000reported deaths due to complications of RHD .The underlying mechanism of the development of RF/RHD is poorly understood. However, the proposed hypothesis in the development of RF/RHD is the autoimmune reaction due to molecular mimicry between different GAS and host proteins . Host adaptive and innate immune systems actively participate in the regulation of autoimmune diseases and adjunct the progression of RF/RHD pathogenesis.

An important component of the innate immune system is NK (Natural killer) cells comprising 10-15% of total peripheral blood lymphocytes. NK cells are instrumental in playing a decisive role in immune activation and regulation. Upon activation, NK cells trigger subsets of T-cells followed by releasing cytokines and chemokines for the clearance of pathogens. During the initial stages of infection, NK cells secrete interferon-γ (IFN-γ), which triggers expression of MHC class I and class II on antigen presenting cells and initiates differentiation of CD4+ T cells to Th1 cells. 

They sequentially produce IL-2 and IFN-γ, which induce the synthesis cytokines and promote the proliferation of NK cells. NK cells expresses KIR (killer cell immunoglobulin like receptor) on their surface and are divided into activating, inhibitory, pseudo and framework genes. KIR molecules target class-I human leukocyte antigen (HLAs) during the time of NK cell inhibition. Continuous expression of inhibitory and activating genes interacts with HLA class- II molecule and subsequently generates signals to eliminate the cells lacking ligands for the KIR inhibitory receptor. HLA class-II molecules, which have been found to be associated with RHD, are targeted by the KIR and subsequently regulate the function of NK cells. Read more.............