What causes reactive arthritis?

Currently, reactive arthritis mainly includes diseases associated with intestinal and genitourinary infections associated with the histocompatibility antigen B27 (HLA-B27).

Two groups of arthritis:

• genitourinary;
• postenterocolitic.

Causes of genitourinary reactive arthritis:

• Chlamydia trachomatis (Cl. Trachomatis, serovar D, K);
• ureaplasma.

Causes of postenterocolitic reactive arthritis:

• Yersinia (Y. enterocolitica serotype 03 and 09, Y. pseudotuberculosis);
• salmonella (S. enteritidis, S. oranienburg, S. typhimurium);
• Shigella (S.flexneri 2-2 a);
• campylobacter (Campylobacter jejuni).

Respiratory tract infections associated with Mycoplasma pneumonia and especially Chlamydia pneumonia are common causes of reactive arthritis.

There is evidence of a link between reactive arthritis and intestinal infection caused by Clostridium difficile and some parasitic infections. However, there is no evidence of a link between these reactive arthritis and HLA-B27.

Currently, one of the most common causes of reactive arthritis is chlamydial infection. In the structure of reactive arthritis, chlamydial arthritis accounts for up to 80%.

Sources of infection in chlamydia are humans, mammals, and birds. Humans become infected with C. pneumoniae and C. psittaci by airborne droplets and airborne dust. C. trachomatis is transmitted sexually, vertically, by contact and household means, when the fetus passes through the infected birth canal of the mother. In childhood, sexual transmission is not relevant. Reactive arthritis can develop when infected with all types of chlamydia.

Immune response to the introduction of a microorganism:

• activation of macrophages;
• local formation of secretory IgA (half-life 58 days);
• activation of the cellular link of immunity;
• production of IgM antibodies against chlamydial lipopolysaccharide (genus-specific antigen) within 48 hours after infection (half-life 5 days);
• synthesis of IgG antibodies against chlamydial lipopolysaccharide from the 5th to the 20th day after infection (half-life 23 days);
• synthesis of IgG antibodies to the main protein of the outer membrane (species-specific antigen) after 6-8 weeks.

In patients with chronic chlamydial reactive arthritis, abnormalities in the immune response are detected: a disturbance in the ratio between T-suppressors and T-helpers (a decrease in the number of T-helpers), a marked decrease in the relative and absolute number of B-cells, and a decrease in the number of natural killer cells.

All changes in the immune response of the patient's body contribute to the chronicity of the process. In the implementation of the genetically determined predisposition of an individual to the development of reactive arthritis, the carriage of HLA-B27 is distinguished.

In the development of the disease, infectious (early) and autoimmune (late) phases are distinguished.

Stages of development of chlamydia

Infection is the entry of a pathogen into the mucous membranes.

Primary regional infection - primary damage to target cells. Two different forms of the microorganism (elementary and reticular bodies) participate in this process. Lasts 48-72 hours.

Generalization of the process:

• hematogenous and lymphatic spread of the pathogen;
• multiple epithelial cell lesions;
• the appearance of clinical symptoms.

Development of immunopathological reactions, mainly in children with HLA-B27.

Outcome of the infectious process. The process can stop at one of the phases:

• residual phase (morphological and functional changes are formed in organs and systems; the pathogen is absent);
• chronic chlamydia phase;
• phase of immune autoaggression.

Immune response

The immune response to the introduction of the microorganism is represented by the following actions: activation of macrophages; local formation of secretory IgA (half-life period of 58 days); activation of the cellular link of immunity; production of IgM antibodies against chlamydial lipopolysaccharide (genus-specific antigen) within 48 hours after infection (half-life period of 5 days). Synthesis of IgG antibodies against chlamydial lipopolysaccharide also occurs between the 5th and 20th day after infection (half-life period of 23 days); synthesis of IgG antibodies to the main protein of the outer membrane (species-specific antigen) after 6-8 weeks.

The production of antibodies, as well as phagocytosis by macrophages, is possible only when the chlamydial cell is in the elementary body stage in the intercellular space. To completely get rid of chlamydia, antibodies are not enough. When chlamydia is in the reticular body stage inside the cell, it is completely inaccessible to both antibodies and lymphocytes and macrophages. Therefore, with a sluggish or asymptomatic process, the amount of antibodies in the blood is usually small.

In patients with chronic chlamydial reactive arthritis, abnormalities in the immune response are detected, namely: a violation of the ratio between T-suppressors and T-helpers (a decrease in the number of T-helpers), a marked decrease in the relative and absolute number of B-cells, and a decrease in the number of natural killer cells.

All of the above changes in the immune response of the patient’s body contribute to the development of chronicity of the process.

Pathogenesis of reactive arthritis

In the origin of reactive arthritis associated with intestinal infection, the main role is given to infection and genetic predisposition. However, the true nature of the relationship between the micro- and macroorganism is still unclear.

"Arthritogenic" microorganisms penetrate the intestinal mucosa and multiply inside polymorphonuclear leukocytes and macrophages. Subsequently, bacteria and their metabolic products penetrate from the primary focus into target organs. According to experimental studies, microorganisms are found for the longest time in cells expressing HLA-B27.

The role of HLA-B27 in the development of reactive arthritis is not fully understood. This antigen belongs to class 1 of the leukocyte antigens of the human major histocompatibility complex (HLA), found on the surface of most cells in the body (including lymphocytes, macrophages) and involved in the implementation of the immune response. It is assumed that HLA-B27 causes the development of an abnormal immune response to pathogenic intestinal and urogenital microflora. Antibodies that cross-react with HLA-B27 are sometimes found in the blood serum of patients. The histocompatibility antigen B27 gives cross-serological reactions with chlamydia and some gram-negative enterobacteria, which is due to the phenomenon of microbial antigenic mimicry. According to this hypothesis, the cell wall of a number of intestinal bacteria and chlamydia contains proteins containing fragments structurally similar to individual sections of the HLA-B27 molecule. It is assumed that cross-reacting antibodies are capable of exerting a damaging effect on the body's own cells that express a sufficient number of HLA-B27 molecules. On the other hand, it is believed that such cross-reaction prevents the implementation of an adequate immune response against intracellular parasites and their effective elimination, contributing to the persistence of infection.

The importance of genetic factors in the pathogenesis of reactive arthritis is evidenced by their close association with HLA-B27, which is detected in urinary arthritis in 80-90% of cases and somewhat less frequently in postenterocolitic arthritis (the hypothesis of microbial mimicry).