Drug-induced autoimmune reactions

Effect of medications on autoimmunity

Certain pharmacological drugs can act as triggers that disrupt immune system tolerance and initiate the production of autoantibodies.

• Autoimmune hemolytic anemia: in this case, the main target for the immune attack is antigen D, which is a key component of the Rh factor system.
• Procainamide: the use of this antiarrhythmic agent is associated with the risk of developing systemic autoaggression. In severe cases, the pathology progresses up to the formation of a full-blown lupus-like syndrome.
• Isoniazid: an antituberculosis drug capable of inducing the synthesis of antinuclear antibodies. Clinically, this condition often manifests as polyarthritis.

Genetic predisposition and MHC-I

The development of autoimmune reactions is largely determined by heredity. Compelling evidence for this comes from family and twin studies. For example, in type 1 diabetes mellitus (T1DM), the concordance rate (coincidence of disease) among monozygotic twins reaches 35–50%. At the same time, in dizygotic twins, this figure is significantly lower, at only 5–6%.

Of particular importance is the association of diseases with MHC-I molecules (in humans, HLA-I). This link is typical for autoimmune pathologies mediated by cytotoxic T cells. The highest relative risk indicators are characteristic of this group:

1. Ankylosing spondylitis: demonstrates a very close association with the carriage of the HLA-B27 allele. The relative risk of developing the disease in this case reaches 87.4%.
2. Acute anterior uveitis: is also associated with the HLA-B27 allele, although the relative risk here is 10%.

Association with MHC-II and molecular mechanisms

The link with MHC-II molecules (HLA-II) is much more common, although relative risk values are generally lower than in the case of MHC-I.

• In diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune toxic goiter, and Hashimoto's thyroiditis, the level of association with HLA molecules ranges from 3 to 6%.
• Goodpasture syndrome is characterized by an association with the HLA-DR2 allele at a level of 16%.

In many cases (especially in type 1 diabetes), the link between the disease and HLA-DR alleles is primarily mediated by their linkage disequilibrium with HLA-DQ alleles.

Molecular features of HLA-DQ in type 1 diabetes

Critically important for the development of diabetes is the 57th position in the DQβ1 chain molecule:

• In healthy Caucasians, this position contains an aspartic acid residue.
• In patients with insulin-dependent diabetes (T1DM), this position is occupied by valine, serine, or alanine residues.
• Experimental data support this fact: in mouse strains not prone to autoimmunity, aspartic acid is located at the 57th position. In the NOD mouse strain (Non-obese diabetic, characterized by a high rate of spontaneous type 1 diabetes), a serine residue is located there.

Mechanism of association: The nature of the link with MHC-II is similar to the control of any immune response. The higher the affinity of the peptide-binding groove of HLA molecules for immunogenic peptides of a specific autoantigen, the higher the risk of developing an immune response to this peptide and triggering the autoimmune process.

The role of non-MHC genes

The development of autoimmune diseases is not limited solely to the effects of the MHC complex. The influence of non-MHC genes is clearly evident in the example of rheumatoid arthritis. Although the disease is associated with HLA-DRB1 and HLA-DRB4 alleles, it is also linked to the following genes:

• PTPN22: encodes intracellular protein tyrosine phosphatase 22.
• CIITA: determines the level of MHC-II molecule expression on cells.
• PADI4: encodes the enzyme peptidylarginine deiminase 4. This enzyme performs post-transcriptional modification of proteins, consisting of the replacement of arginine with citrulline.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of formation of the peptide-binding groove of HLA molecules
• Pathogenesis of antinuclear antibody formation during isoniazid administration
• The role of the enzyme peptidylarginine deiminase 4 and the protein citrullination process in rheumatoid arthritis
• Features of the immune status of NOD mice and the pathogenesis of spontaneous diabetes

Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.