Selective immunoglobulin A deficiency: symptoms, diagnosis, treatment

Among the known immunodeficiency conditions, the most common in the population is selective immunoglobulin A (IgA) deficiency. In Europe, its frequency is 1/400-1/600 people, in Asian and African countries the frequency is somewhat lower.

Selective deficiency is considered to be a condition in which the level of serum IgA is less than 0.05 g/l with normal quantitative indicators of other parts of the immune system.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Pathogenesis of selective immunoglobulin A deficiency

The molecular genetic basis of IgA deficiency is still unknown. It is assumed that the pathogenesis of the defect is due to a functional defect of B cells, as evidenced, in particular, by a decrease in IgA-expressing B cells in patients with this syndrome. It has been shown that in these patients, many IgA-positive B lymphocytes have an immature phenotype, expressing both IgA and IgD. This is probably due to a defect in factors affecting the functional aspects of switching the expression and synthesis of IgA by B cells. Defects in both cytokine production and disturbances in the response of B cells to various mediators of the immune system can contribute. The role of cytokines such as TGF-b1, IL-5, IL-10, as well as the CD40-CD40 ligand system is considered.

Most cases of IgA deficiency are sporadic, but familial cases have been reported, where the defect can be traced through many generations. Thus, 88 familial cases of IgA deficiency have been described in the literature. Autosomal recessive and autosomal dominant forms of inheritance of the defect, as well as an autosomal dominant form with incomplete expression of the trait, have been noted. In 20 families, selective IgA deficiency and common variable deficiency (CVID) were simultaneously observed in different members, which suggests a common molecular defect in these two immunodeficiency states. Recently, researchers have become increasingly convinced that selective IgA deficiency and CVID are phenotypic manifestations of the same, as yet unidentified, genetic defect. Since the gene affected by IgA deficiency is unknown, several chromosomes are being studied that may be involved in the process.

The main attention is paid to chromosome 6, where the genes of the major histocompatibility complex are located. Some works indicate the involvement of MHC class III genes in the pathogenesis of IgA deficiency.

Deletions of the short arm of chromosome 18 occur in half of cases of IgA deficiency, but the exact location of the defect in most patients has not been described. In other cases, studies have shown that the location of the deletion of the arm of chromosome 18 does not correlate with the phenotypic severity of the immunodeficiency.

Symptoms of Selective Immunoglobulin A Deficiency

Despite the high prevalence of such an immunodeficiency as Selective IgA deficiency, people with this defect often have no clinical manifestations. This is probably due to various compensatory capabilities of the immune system, although this question remains open today. With clinically expressed selective IgA deficiency, the main manifestations are bronchopulmonary, allergic, gastrointestinal and autoimmune diseases.

Infectious symptoms

Some studies have noted that respiratory tract infections are more common in patients with IgA deficiency and reduced or absent secretory IgM. It is possible that only the combination of IgA deficiency and one or more IgG subclasses, which occurs in 25% of cases in patients with IgA deficiency, leads to serious bronchopulmonary diseases.

The most common diseases associated with IgA deficiency are upper and lower respiratory tract infections. In such cases, the causative agents of infections are mainly low-pathogenic bacteria: Moraxella catharalis, Streptococcus pneumonia, Hemophilus influenzae, which often cause otitis, sinusitis, conjunctivitis, bronchitis and pneumonia in these patients. There are reports that for the clinical manifestation of IgA deficiency, a deficiency of one or more IgG subclasses is necessary, which occurs in 25% of cases of IgA deficiency. Such a defect leads to serious bronchopulmonary diseases, such as frequent pneumonia, chronic obstructive pulmonary diseases, chronic bronchitis, bronchiectasis. The most unfavorable is considered to be a combined deficiency of IgA and IgG2 subclass, which, unfortunately, is most often encountered.

Patients with selective IgA deficiency often suffer from various gastrointestinal diseases of both infectious and non-infectious genesis. Thus, Gardia Lamblia infection (giardiasis) is common among these patients. Other intestinal infections are also common. Probably, a decrease in secretory IgA, which is part of local immunity, leads to more frequent infection and proliferation of microorganisms in the intestinal epithelium, as well as to frequent reinfection after adequate treatment. A consequence of chronic intestinal infection is often lymphoid hyperplasia, accompanied by malabsorption syndrome.

Gastrointestinal lesions

Lactose intolerance is also more common in selective IgA deficiency than in the general population. The various diarrhoea associated with IgA deficiency, nodular lymphoid hyperplasia, and malabsorbcil are usually difficult to treat.

The frequent association of celiac disease and IgA deficiency is noteworthy. Approximately 1 in 200 patients with celiac disease have this immunological defect (14,26). This association is unique, since no association of gluten enteropathy with any other immunodeficiency has been identified so far. A combination of IgA deficiency with autoimmune diseases of the gastrointestinal tract has been described. Such conditions as chronic hepatitis, biliary cirrhosis, pernicious anemia, ulcerative colitis and enteritis are common.

Allergic diseases

Most clinicians believe that IgA deficiency is accompanied by an increased frequency of almost the entire spectrum of allergic manifestations. These are allergic rhinitis, conjunctivitis, urticaria, atopic dermatitis, and bronchial asthma. Many specialists claim that bronchial asthma in these patients has a more refractory course, which may be due to the development of frequent infectious diseases that aggravate asthma symptoms. However, no controlled studies have been conducted on this topic.

[ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]

Autoimmune pathology

Autoimmune pathology affects not only the gastrointestinal tract of patients with IgA deficiency. Often these patients suffer from rheumatoid arthritis, systemic lupus erythematosus, autoimmune cytopenias.

Anti-IgA antibodies are found in patients with IgA deficiency in more than 60% of cases. The etiology of this immune process is not fully understood. The presence of these antibodies may cause anaphylactic reactions when these patients are transfused with IgA-containing blood products, but in practice the frequency of such reactions is quite low and is about 1 per 1,000,000 blood products administered.

[ 11 ], [ 12 ], [ 13 ]

Diagnosis of selective immunoglobulin A deficiency

When studying humoral immunity in children, it is quite common to encounter a reduced level of IgA against the background of normal IgM and IgG indicators. Transient IgA deficiency is possible, in which serum IgA levels are usually within 0.05-0.3 g/l. This condition is most often observed in children under 5 years of age and is associated with the immaturity of the immunoglobulin synthesis system.

In partial IgA deficiency, the serum IgA level, although lower than age-related fluctuations (less than two sigma deviations from the norm), still does not fall below 0.05 g/l. Many patients with partial IgA deficiency have normal levels of secretory IgA in saliva and are clinically healthy.

As noted above, selective IgA deficiency is defined as serum IgA levels below 0.05 g/l. In such cases, a decrease in secretory IgA is almost always determined. The content of IgM and IgG may be normal or, less commonly, elevated. A decrease in individual IgG subclasses, especially IgG2 and IgG4, is also common.

[ 14 ]

Treatment of selective immunoglobulin A deficiency

There is no specific treatment for IgA deficiency, since there are no drugs that activate IgA-producing B cells. Theoretically, infusion of serum IgA or IgA-containing plasma can temporarily correct IgA deficiency, but it is necessary to take into account the high risk of developing anaphylactic reactions in sensitized patients with anti-IgA antibodies. Patients with severe infectious pathology against the background of IgA deficiency associated with a deficiency of IgG subclasses, or with a decrease in the specific antibody response to bacterial and vaccine antigens, are indicated for intravenous administration of immunoglobulin with a minimal IgA content, or its complete absence in the drug.

Non-infectious diseases in patients with IgA deficiency are treated in the same way as in normal patients. For example, patients with systemic lupus erythematosus and IgA deficiency respond well to immunosuppressive therapy. Patients with IgA deficiency and bronchial asthma are treated according to standard schemes. However, resistance to therapy is more common among such patients, possibly due to the development of concomitant infections.

Forecast

In general, the prognosis for the disease is favorable; life-threatening complications develop infrequently.

[ 15 ]