Genetic and Environmental Factors in Autoimmunity

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Questions and Answers

Which drug is NOT associated with drug-induced lupus?

Procainamide

Aspirin (correct)

Isoniazid

Hydralazine

What type of hypersensitivity is primarily mediated by antibodies in autoimmune diseases?

Type III hypersensitivity

Type IV hypersensitivity

Type I hypersensitivity

Type II hypersensitivity (correct)

Which of the following environmental factors may increase the risk of developing rheumatoid arthritis?

Cold temperatures

Smoking (correct)

High altitude

High humidity

What HLA type has a strong link to autoimmune disease development?

HLA-DR Signup and view all the answers

Which of the following infections is NOT highlighted as a contributing factor to autoimmune disease?

E. coli Signup and view all the answers

Which of the following is NOT a gene associated with autoimmune diseases (ADs)?

HLA Signup and view all the answers

What is the primary reason for suggesting that Crohn's disease is a disorder of mucosal immune dysregulation?

Over-responsiveness of CD4 T cells to certain bacterial species in the gut microbiota. Signup and view all the answers

Which of the following scenarios is NOT a characteristic example of how genetic factors might contribute to autoimmunity?

Mutations in the HLA gene leading to a decreased presentation of self-antigens to T cells. Signup and view all the answers

What is a possible explanation for the observation that certain autoimmune diseases, such as Multiple Sclerosis (MS), are more common in individuals living further north in the Northern Hemisphere?

Exposure to environmental factors, such as sunlight, influences immune responses. Signup and view all the answers

Which statement best describes the genetic factors related to autoimmunity?

Some individuals are genetically predisposed to autoimmunity. Signup and view all the answers

Which of the following statements about HLA and autoimmune diseases is true?

There is a clear association between certain HLA alleles and autoimmune diseases. Signup and view all the answers

What role do environmental factors play in autoimmunity?

They contribute to the timing and expression of autoimmune diseases in genetically predisposed individuals. Signup and view all the answers

How have gene knockout (KO) mice contributed to our understanding of autoimmunity?

They have helped identify gene pathways that might contribute to autoimmunity. Signup and view all the answers

Which of the following best reflects the complexity of MHC genotype associations with autoimmune diseases?

MHC genes can both increase and decrease disease risk. Signup and view all the answers

Study Notes

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.

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Description

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.