HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile

Abstract

The MHC in humans encodes the most polymorphic genes, the HLA genes, which are critical for the immune system to clear infection. This can be attributed to strong selection pressure as populations moved to different parts of the world and encountered new kinds of infections, leading to new HLA class II alleles. HLA genes also have the highest relative risk for autoimmune diseases. Three haplotypes, that is, HLA-DR2DQ6, DR4DQ8, and DR3DQ2, account for HLA association with most autoimmune diseases. We hypothesize that these haplotypes, along with their multiple subtypes, have survived bottlenecks of infectious episodes in human history because of their ability to present pathogenic peptides to activate T cells that secrete cytokines to clear infections. Unfortunately, they also present self-peptides/mimics to activate autoreactive T cells secreting proinflammatory cytokines that cause autoimmune diseases.

Figure 1

Evolution of MHC class II molecules based on their ability to clear different kind of infections. During evolution, MHC class II molecules might have been selected on the basis of their ability to clear particular types of pathogens through a cytokine network. Because IFN-γ has an important role in clearance of viral and intracellular infections, class II molecules such as HLA-DQ6 (DQB1*0601) and DRβ1*0402 might have been selected on the basis of their ability to induce IFN-γ or TGFβ and IL-10 from CD4 T cells. Since clearance of extracellular bacterial and fungal infection requires Th17 cytokine IL-17, class II molecules such as DQ8 (DQB1*0302) were selected for their ability to induce production of IL-17 from CD4 T cells. At the same time, HLA-DR molecules were able to take care of both kinds of infection; however, they did so at lower levels because of their ability to produce moderate amounts of both IFN-γ and IL-17 compared with HLA-DQ molecules.

Figure 2

HLA class II alleles predispose to autoimmune diseases through secretion of proinflammatory cytokines. HLA-DR2, DR3, DR4, DQ6 (0602), and DQ8 (0302) alleles are associated with development of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus. These molecules activate autoreactive CD4 T cells, secreting proinflammatory cytokine such as IL-17 and IFN-γ. In a disease-prone haplotype, both class II molecules synergize to induce more severe disease through production of increased levels of proinflammatory cytokines, such as IFN-γ and IL-17. Heterozygosity for 2 disease-prone haplotypes results in a cascade of proinflammatory cytokines.

Figure 3

Protective class II haplotypes can modulate the cytokine network. HLA-DQ6 (0601) and DR4 (0402) alleles are associated with protection from multiple sclerosis and rheumatoid arthritis, respectively. The studies done with use of single- and double-HLA transgenic mice have suggested that in protective alleles, protection is mediated through production of anti-inflammatory cytokines. DQ6 (0601) molecules protect from multiple sclerosis through anti-inflammatory IFN-γ, while HLA-DR4 (0402) modulate rheumatoid arthritis through production of anti-inflammatory IL-10 and TGF-β.