5 Genetic and Environmental Contributions to Rheumatologic Diseases

Though the exact underlying pathophysiology of most immune-mediated diseases remains unclear, there is growing evidence to support an interplay of underlying genetic as well as environmental triggers that lead to the initiation and perpetuation of an undesirable immune response.  We reviewed some of these general mechanisms related to infection back in I&I.

• Molecular Mimicry: similarity between an antigen in a pathogen and self tissue leads to ongoing immune response to self tissue. eg: rheumatic fever
• Bystander Activation: loss of ‘anergy’ caused by increased expression of co-stimulatory molecules leads to inappropriate activation of adaptive cells that recognize self antigen

Aside from infectious triggers, other environmental inputs that may lead to aberrant immune responses include the effects of inhalants, like tobacco smoke or the effects of certain drugs/medications.

In terms of genetic contributions to immune-mediated diseases, most immune-mediated diseases are thought to be examples of complex so called ‘polygenic’ traits. It’s likely that a combination of gene-gene and gene-environment interactions leads to a loss of self-tolerance.  Some of the most frequently implicated genetic variants in many autoimmune disorders are HLA-antigens.  Remembering back to I&I, HLA (human leukocyte antigens), also known as Major Histocompatibility Molecules (MHC) are the specialized antigen presenting platforms used by cells to display peptides to the T-cells of our adaptive immune system.

• MHC-I: expressed on all nucleated cells, displays antigens from the cytosol or ‘self’
• MHC-II: only expressed on professional antigen presenting cells (macrophages, dendritic cells, B-cells), display antigens phagocytosed from the environment

Expression of these molecules is co-dominant (meaning alleles from both parents are expressed) and each MHC can display multiple but finite array of antigens. Not surprisingly, certain changes in sequence of MHC/HLA genes may predispose a given host to the tendency towards loss of tolerance. The following specific variants are associated with demonstrable increased risk of certain autoimmune diseases and are worth knowing for the boards: (for MJBS please know the risks for the diseases we cover in our Session Level Objectives)