Basic concepts of autoimmunity
Immunological tolerance is the absence of a reaction to an antigen induced by the exposure of specific lymphocytes to that antigen. Autotolerance is a specific case: the absence of an immune response against the body's own antigens. When autotolerance mechanisms fail, autoimmunity develops—an immune response against the body's own healthy cells and tissues.
Confirmation of an autoimmune disease requires three criteria to be met:
- presence of an immune response specifically directed against an autoantigen or self-tissue;
- the reaction is a primary process, rather than secondary to tissue damage;
- absence of any other identified cause of the disease.
The diagnosis is made only after excluding other potential causes, as laboratory signs of autoimmunity can accompany other pathological processes as well.
Central mechanisms of autotolerance
Central tolerance is established in the primary lymphoid organs: the thymus for T lymphocytes and the red bone marrow for B lymphocytes.
In the thymus, negative selection takes place: dendritic cells acting as professional antigen-presenting cells (along with macrophages and some B lymphocytes) present autoantigens whose expression is regulated by the AIRE gene. The fate of a thymocyte is determined by the binding strength of its receptor to the autoantigen:
- strong binding — cell apoptosis (deletion);
- intermediate binding — differentiation into a regulatory T cell (Treg) bearing the CD25 marker;
- weak or absent binding — the cell passes positive selection and becomes a mature CD4+ T helper or CD8+ T cytotoxic lymphocyte.
In the bone marrow, autoreactive B lymphocytes undergo receptor editing: rearrangement of immunoglobulin genes to form a new specificity that is not directed against autoantigens. If editing is impossible, the cell is eliminated via apoptosis. Cells incapable of assembling a functional receptor at the pro-T or pro-B stage also die.
Peripheral mechanisms of autotolerance
Some autoreactive lymphocytes escape central selection and enter peripheral lymphoid organs, where the "second line" of control operates.
- Anergy is the functional inactivation of a lymphocyte. The antigen-presenting cell presents the autoantigen in a complex with MHC, but fails to provide the second signal—costimulation. In the T lymphocyte, ubiquitin ligase is activated, cleaving signaling pathway components, and the cell stops responding to the antigen. This state is potentially reversible.
- Suppression by T regulatory cells. CD25+ Tregs expressing the IL-2 receptor and the FOXP3 transcription factor recognize the same autoantigen as the autoaggressive lymphocyte and drive it into a state of anergy or apoptosis. Tregs control the strength and duration of the immune response by regulating T helpers and T cytotoxic cells.
- Deletion via activation-induced cell death (AICD). Upon repeated activation in an autoaggressive T lymphocyte, the synthesis of anti-apoptotic proteins decreases while the expression of Fas (CD95) increases; the interaction of Fas with Fas ligand triggers a caspase cascade and cell death.
Mutations in the FOXP3 gene lead to the development of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, whereas Fas/FasL defects result in lymphoproliferative autoimmune conditions.
Causes of auto-tolerance breakdown
The development of an autoimmune disease can be triggered by various mechanisms:
- appearance of new antigenic determinants upon tissue damage or modification of the antigen carrier;
- alteration of membrane antigen structure under the action of viruses or chemical agents;
- cross-reactivity (molecular mimicry): antibodies against microbial antigens react with self-tissues. A classic example is acute rheumatic fever, where antibodies against Streptococcus pyogenes attack myocardial and valve antigens;
- acute tissue trauma with the release of sequestered ("privileged-site") antigens;
- polyclonal B cell activation by mitogens with the production of a broad spectrum of autoantibodies;
- genetic defects in regulatory molecules: AIRE, FOXP3, Fas/FasL, complement system components;
- disturbances in apoptosis and selection, allowing autoreactive cells to reach the periphery.
Classification and examples of autoimmune diseases
Based on the distribution of lesions, autoimmune diseases are divided into organ-specific and systemic (generalized).
- Organ-specific — the immune response is directed against a single organ. Type 1 diabetes mellitus: autoreactive T cells and antibodies are specific to the β-cells of the pancreatic islets of Langerhans. Hashimoto's autoimmune thyroiditis, Graves' disease, and myasthenia gravis also belong to this group.
- Systemic — the targets are antigens widely distributed throughout the body. Systemic lupus erythematosus: antibodies are formed against double-stranded DNA, nucleoproteins, platelets, and erythrocytes, leading to multiorgan involvement. Rheumatoid arthritis and systemic sclerosis also belong to this group.
Key points
- Autotolerance is maintained by central (thymus, bone marrow) and peripheral mechanisms.
- In the thymus, the AIRE gene ensures the presentation of autoantigens and the negative selection of autoreactive T cells.
- Intermediate binding to an autoantigen directs the thymocyte into the CD25+ FOXP3+ Treg lineage.
- In the periphery, anergy, Treg suppression, and activation-induced cell death via Fas/FasL operate.
- Costimulation is an obligatory second signal for T lymphocyte activation; its absence leads to anergy.
- Mutations in FOXP3, AIRE, Fas/FasL are genetic causes of autoimmune syndromes.
- Molecular mimicry (for example, in streptococcal infection) is a frequent trigger of autoimmunity.
- Autoimmune diseases are divided into organ-specific (type 1 DM) and systemic (SLE).