Genetic and Environmental Factors in Autoimmunity

Genetic/Environmental Basis of Autoimmunity

• Autoimmunity (AD) development is influenced by a combination of genetic and environmental factors.
• Certain HLA alleles are strongly linked to AD development.
• Non-HLA genes also play a role in AD susceptibility.
• Environmental factors significantly influence AD development and should not be overlooked.
• Both B and T cells contribute to the pathogenic mechanisms of autoimmune reactions.

Aims & Learning Outcomes

• The aim of the session is to promote understanding of how genetics and environmental factors influence autoimmunity.
• By the end of the session, learners should have a good understanding of the following:
  • HLA's role in susceptibility to autoimmunity.
  • HLA and non-HLA genes involved in autoimmunity.
  • Factors influencing autoimmunity from the environment.
  • Basics of autoimmune pathogenic mechanisms.

Genetics & Environment

• Some individuals are predisposed genetically to autoimmunity.
• Autoimmune diseases (ADs) can run in families.
• Examples include type 1 diabetes.
• Animal models (e.g. NOD mice) help investigate ADs. Not all mice in the same colony will develop the disease at the same time, highlighting the role of environmental factors.
• Gene knockout (KO) mice provide insights into gene pathways that contribute to autoimmunity.
• Genome-wide association studies (GWAS) also offer valuable insights.

HLA Type

• Clear associations exist between specific HLA types and autoimmune diseases.
• The strongest link is between MHC class II alleles (HLA-DRβ4-RA) and several diseases.
• Some linkage also exists with MHC class I alleles.
• MHC class III alleles are associated with certain diseases in some cases.
• MHC genotype associations with ADs are not surprising.
• MHC genes can both increase and decrease disease risk.

HLA Allele Table

• Presents data on specific HLA alleles' associations with respective diseases and relative risks. (Table presented from the document).

Models to Explain Susceptibility to AD

• Different MHC allelic variants influence how autoantigens are presented to autoreactive T cells.
• MHC alleles play a crucial role in shaping the T-cell repertoire.
• Thymocytes specific for particular autoantigens are generated via positive selection.
• Insufficient expression or poor binding of peptides to self MHC drives negative selection.

Non-HLA Associations

• Most ADs involve multiple susceptibility genes, illustrating a polygenic nature.
• Mutations in specific genes can contribute to the pathogenesis of autoimmunity.
• Genes associated with autoantigen availability and clearance (AIRE-APECED), apoptosis (Fas/FasL-ALPS), co-stimulatory molecules/receptors (CTLA-4, PD-1), and regulatory T cell (Treg) development/function (Foxp3-IPEX) have been identified.

Impairment of Innate Immune Function: Crohn's Disease

• Crohn's disease is characterized by mucosal immune dysregulation.
• An exaggerated response of CD4 T-cells to normal gut flora is observed.
• Inflammatory lesions can involve the entire gastrointestinal (GI) tract.
• Symptoms include fever, abdominal pain, weight loss, fistulas, and bowel abscesses.
• A single gene has been associated with Crohn's disease.

Some Other Influences

• Disease incidence varies geographically. The incidence of diseases such as Multiple Sclerosis (MS) and type 1 Diabetes (DM) in the northern hemisphere is higher than in the southern hemisphere.
• Socioeconomic status, including dietary factors, like gluten intake, can influence AD development.
• ADs occur more frequently in women than in men, suggesting a potential hormonal influence.
• Pregnancy can influence the course of autoimmune diseases like rheumatoid arthritis (RA).
• Age is another influential factor in some cases, exemplified by increasing age often associated with reduced severity of disease.

Drugs, Smoking, and Sunlight

• Some drugs, such as hydralazine, procainamide, and isoniazid, may induce lupus.
• Smoking increases the risk of rheumatoid arthritis (RA) and some autoimmune thyroid diseases (Hashimoto's and Graves').
• Sunlight exposure can contribute by potentially triggering systemic lupus erythematosus (SLE) lesions.
• Infections, such as EBV, mycoplasma, streptococci, Klebsiella, and malaria have demonstrated a correlation with autoimmune diseases.

Mechanisms of Tissue Damage in AD

• AD tissue damage is classified according to the hypersensitivity reaction type.
  • Type II: antibody-mediated.
  • Type III: immune complex-mediated.
  • Type IV: T-cell-mediated.
• Overlap between antibody and T-cell mediated tissue damage is common.
• Tissue damage is amplified by a constant supply of new autoantigens.

Mechanism of Autoimmune Disease Diagram

• Explains the mechanisms of antibody deposition (complement and Fc receptor activation) and immune complex-mediated tissue injury with neutrophils and inflammatory cells.

Mechanisms of Tissue Damage in AD Summary Diagrams

• Shows cytokine-mediated inflammation and T-cell-mediated cytotoxicity as key mechanisms in tissue injury.

Summary

• AD development depends on a complex interplay between genes and the environment.
• HLA alleles are strongly linked with AD development.
• Several Non-HLA genes have been associated with AD.
• Environmental factors play a crucial role in AD.
• Both B and T cells contribute to pathogenic mechanisms in AD reactions.

This quiz explores how both genetic predispositions and environmental influences contribute to the development of autoimmune diseases. Participants will learn about specific HLA alleles, non-HLA genes, and the roles of B and T cells in autoimmune mechanisms. Understanding these factors is crucial for recognizing susceptibility to autoimmune disorders.