Genetics of autoimmune diseases — disorders of immune homeostasis

Key Points

  • Complex and diverse mechanisms have evolved to regulate the immune system and prevent it from inappropriately turning against the self. Overall, autoimmunity can be viewed as an alteration in the normal homeostatic mechanisms that regulate self–non-self discrimination.

  • The immune system comprises two interacting systems that are based on innate and adaptive immune responses. Innate responses are immediate and generally use pre-formed recognition structures, whereas adaptive immunity involves the production and selection of specific recognition structures that develop following exposure and persist as a memory response.

  • A number of genes involved in adaptive immunity have been implicated in autoimmune diseases. Several of these genes regulate T-cell tolerance to self, and give rise to rare and highly penetrant Mendelian disorders. Other genes are common and have more subtle 'threshold' effects on T-cell reactivity. In general, T-cell tolerance is effected 'centrally' in the thymus, or peripherally through the action of regulatory T cells or other mechanisms.

  • The genetic variants involved in regulating T-cell and B-cell tolerance predispose to multiple autoimmune disorders. This demonstrates that there are common underlying mechanisms for many of these diseases, such as type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis, among others.

  • Recent studies have also demonstrated the involvement of the innate immune system in autoimmunity. In particular, Toll-like receptors have been implicated in the development of B-cell autoimmunity, and genetic associations in Toll-receptor signalling pathways have been found in systemic lupus erythematosus.

  • New gene-identification strategies, such as whole-genome association studies, are likely to reveal many additional genes that predispose to autoimmunity. A consideration of gene–gene and gene–environment interactions will be essential for the proper interpretation of these new genetic findings.

Abstract

In the past few years, our extensive knowledge of the mammalian immune system and our increasing ability to understand the genetic causes of complex human disease have opened a window onto the pathways that lead to autoimmune disorders. In addition to the well-established role of genetic variation that affects the major histocompatibility complex, a number of rare and common variants that affect a range of immunological pathways are now known to have important influences on the phenotypic diversity that is seen among autoimmune diseases. Recent studies have also highlighted a previously unanticipated interplay between the innate and adaptive immune system, providing a new direction for research in this field.

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Figure 1: The innate and adaptive immune systems and the overlap between them.
Figure 2: Central and peripheral tolerance mechanisms.
Figure 3: Co-stimulatory and co-inhibitory molecules set thresholds for T-cell activation.
Figure 4: Regulation of LCK tyrosine kinase activity by PTPN22 and CSK.
Figure 5: Model of innate immune responses in autoimmunity.
Figure 6: Activation of interferon production through TLR7 and TLR9 receptors.

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Acknowledgements

Some of the work described in this Review has been supported by grants from the National Institutes of Health and the National Arthritis Foundation. P.K.G. receives additional support from the Boas family and from the Eileen Ludwig Greenland Center for Rheumatoid Arthritis.

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Correspondence to Peter K. Gregersen.

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DATABASES

OMIM

Addison disease

APS1

Crohn disease

Graves disease

IPEX

myasthenia gravis

SLE

type 1 diabetes

rheumatoid arthritis

FURTHER INFORMATION

International HapMap Project

Glossary

Innate immune system

Nonspecific and phylogenetically ancient mechanisms that form the first line of defence against infection. Innate immune defence is inborn and does not involve memory; it uses a limited set of molecules that generally recognize common molecular patterns found in microorganisms.

Adaptive immune system

A flexible and specific immune response that can adjust to new structures and that retains a memory of prior exposure to these structures. A large and diverse set of recognition molecules — antibodies (produced by B cells) and T-cell receptors — mediate adaptive immune recognition.

Linkage analysis

A method for tracking the transmission of genetic information across generations to identify the map location of genetic loci on the basis of co-inheritance of genetic markers and discernable phenotypes.

Gene association study

A study in which a genetic variant is genotyped in a population for which phenotypic information (such as disease occurrence, or a range of different trait values) is available. If a correlation is observed between the genotype and phenotype, there is said to be an association between the variant and the disease or trait.

Candidate gene

A gene for which there is evidence of its possible role in the trait or disease that is under study.

T cells

Lymphocytes that have important roles in the primary immune response. Effector T cells fall into two classes — CD8+ killer or cytotoxic T cells, which destroy infected cells, and CD4+ or helper T cells, which regulate the function of other lymphocytes. A third class, regulatory T cells, regulate the self reactivity of effector T cells in the periphery.

Systemic lupus erythematosus

The prototypical autoimmune disease in which antibodies are produced to DNA and a variety of other self constituents. The disease has highly variable manifestations and can be mild or lead to widespread inflammation and tissue destruction of important organ systems.

Tolerance

A specific unresponsiveness of the adaptive immune system to particular antigens in an otherwise immunocompetent organism. In the absence of autoimmunity, tolerance to self antigens is characteristic of the normal immune system.

Type I diabetes

An autoimmune disorder in which insulin-producing islet cells are destroyed by the immune system, leading to insulin deficiency. Onset is usually in childhood or adolescence.

Myasthenia gravis

An autoimmune disorder in which antibodies to the acetylcholine receptor disrupt neuromuscular transmission leading to symptoms of weakness.

Rheumatoid arthritis

A chronic inflammatory disorder of synovial joints and surrounding tissues. It often leads to bone and cartilage destruction if left untreated.

Whole-genome association studies

Studies in which associations between genetic variation and a phenotype of interest (for example, disease) are identified by genotyping cases and controls for a set of polymorphic markers that capture genetic variation across the entire genome.

Florid lymphoproliferation

Extensive proliferation of lymphoid elements, usually either T cells or B cells.

Odds ratio

A measure of relative risk that is usually estimated from case–control studies.

Addison disease

A condition resulting from inadequate production of cortisol by the adrenal glands owing to adrenal destruction by autoimmune mechanisms.

Coeliac disease

An autoimmune disorder induced by exposure to gluten and characterized by damage to all or part of the villi lining the small intestine, leading to malabsorption.

Macrophage

A specialized type of white blood cell that can engulf foreign particles and microorganisms.

Dendritic cells

These cells present antigen to T cells, and stimulate cell proliferation and the immune response.

Memory T cells

T lymphocytes that have been previously exposed to specific antigen and are primed to have an increased response following re-exposure to the same antigen.

Natural killer cell

Large granular non-T, non-B-type lymphocytes. Natural killer cells are important for the early response to viruses. They produce cytokines, kill certain tumour cells and have appropriate receptors for antibody-dependent cell-mediated cytotoxicity.

Humoral

In mammals, humoral immunity describes B-cell-mediated immunity that fights bacteria and viruses in body fluids with antibodies that circulate in blood plasma and lymph.

Ancestry informative markers

A locus with several polymorphisms that exhibit substantially different frequencies between ancestral populations. For example, the Duffy null allele has a frequency of almost 100% of sub-Saharan Africans, but occurs rarely in other populations.

Complement system

A complex protein cascade that is involved in both innate and adaptive immunity. Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway.

Penetrance

The proportion of individuals with a specific genotype who manifest the genotype at the phenotypic level. For example, if all individuals with a specific disease genotype show the disease phenotype, then the genotype is said to be 'completely penetrant'.

Multiple-hypothesis testing

Testing more than one hypothesis within an experiment. As a result, the probability of an unusual result from within the entire experiment occurring by chance is higher than the individual P-value associated with that result.

Prospective cohorts

Individuals who are selected for certain exposure characteristics and can be followed up over time to assess who develops a certain outcome (often disease).

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Gregersen, P., Behrens, T. Genetics of autoimmune diseases — disorders of immune homeostasis. Nat Rev Genet 7, 917–928 (2006). https://doi.org/10.1038/nrg1944

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