by Dr. Adele Visser
Introduction
In essence, autoimmune disease occurs as a result of the loss of immunological tolerance, leading to an immune response against self-molecules. The underlying causes are poorly understood, however certain environmental and genetic factors have been identified. Women account for more than 75% of cases and current data suggest the role of sex hormones in the inception of this class of disorders.
Overview of Autoimmune Disease
Autoimmune disease occurs due to reactivity to self-antigens, which may be specific to organs to more systemic antigens (Figure 1).
Figure 1.
Range of autoimmune diseases with their associated auto-antigens and target repertoire (adapted from reference 1).
Mechanisms of Autoimmune Disease
Auto-reactive immune cells (specifically T and B lymphocytes) are found in healthy individuals and are typically regulated by the actions of immune tolerance. A disruption in this balance manifests as autoimmune disease. Various mechanisms have been described.
It is typically used in the setting of:
I. Release of Isolated Auto-antigens
Certain antigens are found in protected or cryptic sites, where they are not exposed to the immune system as such. Various reactive T-cells are not deleted during thymic training but are not exposed to the antigen itself.
However, upon cellular damage through trauma or viral infection, these antigens may become exposed, triggering an autoimmune response and consequently disease. Diabetes mellitus following infection by Coxackie B viruses serve as an example.
II. Chemical Alteration of Self-peptides
As in the previous mechanism, self-reacting T-cells may be present but not activated. Another stimulus may increase the secretion of IFN-γγ which upregulates the antigen-presenting MHC molecules, enhancing the chances of autoreactivity.
A further example is the induction of a hapten-induced autoimmune response where drugs lead to the development of a self-reactive immune state. The drug molecule binds to a self-antigen, which leads to sufficient alteration to allow for immune stimulation.
III. Molecular Mimicry
Fragments from various infectious agents may show sufficient similarity to self-antigens and thereby induce an immune reaction to both. The membrane proteins from the group B Streptococci show similarity to cardiac myosin and may consequently lead to rheumatic fever. Similar associations have been made with Yersinia enterocolitica and Grave’s disease.
IV. Polyclonal Activators
Again, microbial antigens have been implicated in the activation T-cells which bind to both MCH class II molecules on B-cells, and directly to B-cells themselves. This super-activation leads to the formation of a large repertoire of antibodies, some of which may be self-reactive.
V. Genetic Factors
Genetic association is more frequently seen in organ- specific autoimmune disease. Despite this, concordance rates between identical twins are relatively low, owing to the varied identity of the TCR and Ig genes’ formation due to recombination and somatic hypermutation processes. However, associations are noted with certain MCH haplotypes and may also be found in T-cell Receptor haplotypes.
Conclusion
The highly complicated nature of the human immune system makes a simplistic explanation to autoimmune disease highly improbable. Not only is the disease pathogenesis highly variable, but so also the clinical manifestations and laboratory findings associated there-with. With this in mind, it would be prudent to always employ a multi-disciplinary approach where the clinical features stand central to decision making.
References
- Smit DA, Germolec DR. 1999. Introduction to Immunology and Autoimmunity. Environmental Health Perspectives. 107(5): 661-665
- Hodson R, 2021. Autoimmune disease. Nature. 595, S45 doi: https://doi.org/10.1038/d41586-021-01833-y