The immune system has evolved sophisticated mechanisms to discriminate self from non-self and to regulate the magnitude of immune responses. When these mechanisms fail, the result can be either autoimmunity, where immune responses are directed against self-antigens, or hypersensitivity, where immune responses are excessive, prolonged, or inappropriately targeted against harmless environmental antigens.
Mechanisms of Autoimmunity
Autoimmunity results from a breakdown of self-tolerance mechanisms that normally prevent lymphocytes from attacking self-tissues. Central tolerance eliminates self-reactive T cells during thymic development through negative selection, but this process is incomplete, and some self-reactive T cells escape to the periphery. Peripheral tolerance mechanisms including anergy (functional inactivation), immune suppression by regulatory T cells (Treg), and activation-induced cell death (AICD) normally control these escaped self-reactive cells. Autoimmunity develops when these regulatory mechanisms are overwhelmed or defective. The loss of self-tolerance is multifactorial, involving genetic predisposition, environmental triggers such as infection or tissue injury, and stochastic events. Molecular mimicry occurs when microbial antigens share sequence or structural similarity with self-antigens, activating cross-reactive T or B cells. Epitope spreading refers to the diversification of the autoimmune response from one self-epitope to additional epitopes on the same or different self-proteins as tissue damage releases new antigens.
Genetic Factors in Autoimmunity
Genetic susceptibility to autoimmune diseases involves multiple genes, each contributing modestly to risk. The strongest genetic associations map to the MHC region. Specific HLA alleles are associated with particular autoimmune diseases: HLA-DRB104:01 with rheumatoid arthritis, HLA-DQB102:01 and HLA-DQB103:02 with celiac disease, HLA-DRB115:01 with multiple sclerosis, and HLA-DR3/DR4 with type 1 diabetes. Non-MHC genes also contribute, including PTPN22, which encodes a tyrosine phosphatase that regulates T cell and B cell receptor signaling; CTLA4, an inhibitory receptor that limits T cell activation; IL2RA (CD25), the high-affinity IL-2 receptor α chain essential for Treg function; and PTPN2, involved in cytokine signaling. Many autoimmune risk variants are located in non-coding regulatory regions and affect gene expression levels rather than protein coding. Genome-wide association studies have identified over 200 risk loci for autoimmune diseases, with substantial overlap between different diseases, suggesting shared pathogenic mechanisms.
Type I Hypersensitivity
Type I hypersensitivity, also called immediate or allergic hypersensitivity, is mediated by IgE antibodies and mast cell degranulation. Upon first exposure to an allergen, Th2 cells promote class switching to IgE, which binds to high-affinity FcεRI receptors on mast cells and basophils. Subsequent exposure to the same allergen cross-links surface-bound IgE, triggering mast cell degranulation within minutes, releasing preformed mediators including histamine, tryptase, and heparin. Newly synthesized mediators, including leukotrienes, prostaglandins, and cytokines such as IL-4, IL-5, and IL-13, are also released within hours. Clinical manifestations range from mild allergic rhinitis (hay fever) and urticaria (hives) to severe systemic anaphylaxis characterized by bronchospasm, laryngeal edema, hypotension, and cardiovascular collapse. Allergic asthma involves mast cell degranulation in the lower airways, leading to bronchoconstriction, mucus hypersecretion, and chronic airway inflammation with eosinophil infiltration. Food allergies, including peanut, tree nut, shellfish, and milk allergies, affect approximately 8% of children and 3% of adults and carry the risk of anaphylaxis.
Type II Hypersensitivity
Type II hypersensitivity involves antibody-mediated destruction of cells or tissues, typically through IgG or IgM directed against cell surface or extracellular matrix antigens. Antibody binding can cause cell damage through several mechanisms: complement activation via the classical pathway leading to membrane attack complex formation and cell lysis; opsonization and phagocytosis of antibody-coated cells by macrophages through Fcγ receptors; and antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells. Examples of type II hypersensitivity include autoimmune hemolytic anemia, where antibodies against red blood cell antigens cause complement-mediated lysis; immune thrombocytopenia, with antibodies against platelet glycoproteins; Goodpasture syndrome, where anti-glomerular basement membrane antibodies target type IV collagen in kidney and lung; and pemphigus vulgaris, with antibodies against desmoglein adhesion molecules in the skin. Hemolytic transfusion reactions and hemolytic disease of the newborn (erythroblastosis fetalis) are examples of alloantibody-mediated type II hypersensitivity.
Type III Hypersensitivity
Type III hypersensitivity is mediated by immune complexes formed when antibodies bind soluble antigens in circulation or in tissues. Deposition of immune complexes in blood vessel walls, glomeruli, joints, and other tissues triggers complement activation and recruitment of neutrophils, leading to inflammatory tissue damage. Serum sickness, historically induced by injection of foreign serum proteins, is the prototypical systemic type III reaction. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by antinuclear antibodies and immune complex deposition in multiple organs, including glomerulonephritis (kidney), arthritis (joints), serositis (pleura and pericardium), and vasculitis. Arthus reaction is a local type III hypersensitivity caused by injection of antigen into an individual with high levels of circulating antibodies. Post-streptococcal glomerulonephritis results from immune complex deposition in glomeruli following group A streptococcal infection, with antibodies against streptococcal antigens cross-reacting with glomerular components.
Type IV Hypersensitivity
Type IV hypersensitivity, also called delayed-type hypersensitivity (DTH), is mediated by sensitized T cells rather than antibodies and develops 24–72 hours after antigen exposure. CD4+ Th1 cells recognizing the antigen produce IFN-γ and TNF-α, activating macrophages and promoting granuloma formation. The tuberculin skin test (Mantoux test) for latent tuberculosis infection is a classic example: intradermal injection of purified protein derivative (PPD) from Mycobacterium tuberculosis induces local induration at the injection site in sensitized individuals. Contact dermatitis, caused by haptens such as urushiol (poison ivy), nickel, and fragrances, involves CD8+ cytotoxic T cells that kill keratinocytes expressing modified self-peptides, resulting in vesicular skin lesions. Celiac disease is driven by CD4+ T cells recognizing deamidated gluten peptides presented by HLA-DQ2 or HLA-DQ8, producing IFN-γ and causing villous atrophy in the small intestine. Type IV hypersensitivity also underlies granulomatous diseases including tuberculosis, leprosy, and sarcoidosis.
Autoimmune Diseases of Major Organs
Rheumatoid arthritis is a chronic inflammatory disease affecting synovial joints, driven by autoantibodies (rheumatoid factor and anti-citrullinated protein antibodies, ACPA) and Th17-mediated inflammation leading to bone and cartilage destruction. Type 1 diabetes results from autoimmune destruction of pancreatic β cells by CD8+ T cells recognizing insulin and other β cell antigens, leading to insulin deficiency. Multiple sclerosis involves T cell and antibody-mediated demyelination in the central nervous system, with autoreactive T cells recognizing myelin antigens including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). Inflammatory bowel disease, including Crohn disease and ulcerative colitis, results from dysregulated immune responses against commensal gut microbiota in genetically susceptible individuals, with Th17 and Th1 cells driving intestinal inflammation. The common theme across autoimmune diseases is the loss of tolerance to specific self-antigens in genetically predisposed individuals, often triggered by environmental factors such as infection, smoking, or microbiome alterations.
