General Variable Immune Deficiency: Symptoms, Diagnosis, Treatment

Common Variable Immune Deficiency (CVID) is a heterogeneous group of diseases characterized by a defect in the synthesis of antibodies. The prevalence of OVIN varies from 1: 25,000 to 1: 200,000, the sex ratio is the same.

Pathogenesis of total variable immune deficiency

The molecular defect of most patients is unknown, and probably in this group several nosologies are combined. Most cases of OVIN are sporadic, however, family variants are also traced, as well as cases of general variable immune deficiency and selective IgA deficiency in one family, suggesting that these two diseases can be allelic variants of a single gene mutation.

Numerous attempts to discover the genetic basis of the general variable immune deficiency led to the detection of the first defect in this mutation group of the gene for the induced cos-stimulator molecule (1C0S) located on the long arm of the chromosome. ICOS is expressed by activated T lymphocytes, its interaction with its ligand on B lymphocytes is necessary for the late differentiation of B cells and the formation of B memory cells. To date, 9 patients with this mutation have been described.

More recently, in 17 patients with OVIN (of 181 scribbles), a mutation of the gene TNFRSF13B encoding a transmembrane activator and a calcium modulator (TACI) was detected . TACI is expressed in lymphocytes and is important for their interaction with macrophages and dendritic cells.

At the moment, the general variable immune deficiency is attributed by WHO experts to the group of immunodeficiencies with a predominant disruption of the production of antibodies, but a lot of data have been revealed that indicate the damage of T-lymphocytes. Thus, the decrease in the production of immunoglobulins is probably associated with a violation of T-cell regulation of their synthesis, that is, OVIN is to a greater extent a combined immunodeficiency,

Laboratory changes

As a rule, with a general variable immune deficiency, the concentrations of the three main classes of immunoglobulins are reduced; it is possible to reduce only two, for example IgA and IgG or even one IgG. All patients have a violation of specific antibody formation,

The number of B-lymphocytes in most patients is not changed, but often they have an immature phenotype with restriction of hyper mutations, as well as a decrease in the number of B memory cells.

Many patients experience T-lymphopenia, a violation of the CD4 / CD8 ratio (due to a decrease in CD4 + and an increase in CD8 +), a limited repertoire of T lymphocytes. Proliferation of lymphocytes and production of IL-2 under the influence of nonspecific and, especially, specific mitogens are significantly impaired in patients with CVID. There is evidence of a decrease in the expression of the CD40 ligand by activated T cells and signal transmission defects through the costimulatory molecules CD40-CD40L and CD28-B7, which causes a violation of B cell differentiation in some patients with a general variable immune deficiency.

A defect of the macrophage link plays an important role in the development of the cascade of cell disorders with a general variable immune deficiency, as an increase in the number of monocytes containing intracellular IL-12, which is associated with an increase in the number of IFN-y-positive T cells. This imbalance shifts the immune response by the Th1 type and also explains the inability of T cells to generate antigen-specific memory cells and the propensity of patients to develop chronic inflammation and granulomatous complications with a general variable immune deficiency.

In addition, there are data on disturbed maturation and differentiation of dendritic cells, which results in a violation of the antigen presentation necessary for the effective functioning of T-lymphocytes.

Symptoms of general variable immune deficiency

The first symptoms of a general variable immune deficiency can appear at any age, usually the general variable immune deficiency is diagnosed at the age of 20-40 years. In children, the general variable immune deficiency usually debuts in adolescence, but the appearance of the first symptoms is also possible at an early age, as is the case with agammaglobulinemia.

The spectrum of clinical manifestations on the basis of which the general variable immune deficiency can be suspected is very wide: in some patients the first clinical manifestations are repeated pneumonia, others - thrombocytopenic purpura, autoimmune hemolytic anemia, or colitis.

Infectious complications with the general variable immune deficiency are mainly represented by bacterial lesions of the respiratory and gastrointestinal tract, purulent meningitis, giardiasis. Pneumonia is one of the most frequent manifestations of a general variable immune deficiency. They are often accompanied by the formation of bronchiectasis or a tendency to chronic. In addition to banal bacterial, opportunistic infections can also develop in the form of pneumocystis pneumonia.

Patients with OVIN are prone to the development of purulent arthritis caused by mycoplasmas and ureoplasms. Often, septic arthritis develops in patients with ovine, already suffering from rheumatoid arthritis. A case of septic arthritis is described against the background of a generalized infection of Penirittium marneffe, whose treatment with antifungal and replacement therapy has proven effective.

Viral hepatitis (especially hepatitis C) occurs with a general variable immune deficiency severely (sometimes fatal), with severe clinical and laboratory disorders and quickly give complications in the form of chronic active hepatitis and can recur even after liver transplantation. In OVIN, the infection caused by Herpes simplex is often found and can be difficult to carry out .

Patients with CVID, as well as with other forms of humoral defects, are highly sensitive to enteroviruses. Enteroviral encephalomyelitis is extremely difficult and presents a serious threat to life, it is possible enteroviral poliomyelitis - and dermatomyositis-like diseases, skin and mucous membranes.

Other viruses can also cause serious diseases. For example, parvovirus B19 can cause erythroid aplasia.

In addition to infectious lung lesions in patients with CVID, noncaseating granulomas have been described that have much in common with sarcoidosis. Aseptic noncaseating and caseous granulomas can occur in the lungs, skin, liver, spleen. The cause of the development of granulomatous inflammation that occurs in different organs of patients with a general variable immune deficiency is probably a violation of T-cell regulation of macrophage activation.

Autoimmune manifestations are difficult and can determine the prognosis. Sometimes autoimmune disorders are the first clinical manifestations of CVID: arthritis, ulcerative colitis and Crohn's disease, sclerosing cholangitis, malabsorption and enteropathy, systemic lupus erythematosus, nephritis, myositis, autoimmune lung involvement in the form of lymphoid interstitial pneumonitis, neutropenia, thrombocytopenic purpura, hemolytic anemia, pernicious anemia, total alopecia, retinal vasculitis. One patient can develop several autoimmune syndromes at once, for example: arthritis, alopecia and cytopenia, or systemic lupus erythematosus, and later - enteropathy and nephritis.

Gastroenterology pathology occupies a significant place among the symptoms of a general variable immune deficiency. In 25% of cases of general variable immune deficiency, gastroenterological disorders are detected in the form of ulcerative colitis, proctitis and Crohn's disease, nodular lymphoid intestinal hyperplasia, malabsorption, giardiasis, protein-losing enteropathy, sprue-like syndrome, campylobacteriosis and other more rare syndromes. Along with infectious, certainly, the essential role is played also by autoimmune mechanisms of development of gastroenterological lesions.

Patients with OVIN significantly increased the incidence of malignant tumors, sarcoid granulomas and non-malignant lymphoproliferation. With a general variable immune deficiency, an increase in not only the peripheral but also the intrathoracic lymph nodes is often found. When analyzing the incidence of malignant tumors, various tumors were detected in 15% of cases. The increased incidence of non-Hodgkin's lymphomas and adenocarcinomas of the stomach, Hodgkin's lymphomas, intestinal, breast, prostate and ovarian cancers.

Diagnosis of total variable immune deficiency

In connection with the impossibility of carrying out confirmatory molecular genetic studies in the majority of cases of general variable immune deficiency, it is especially important to exclude other causes of hypogammaglobulinemia.

Based on the criteria of the European Society for the Study of Immunodeficiency Viruses (ESID), the diagnosis of a general variable immune deficiency is highly probable with a significant reduction (more than 2 SD from the median) of two or three major immunoglobulin IgG (IgA, IgG, IgM) in persons of both sexes in combination with one of the following:

• the onset of immunodeficiency at the age of more than 2 years;
• absence of isohemagglutinins and / or poor response to vaccines;
• other well-known causes of agammaglobulinemia should be excluded.

Treatment of total variable immune deficiency

As with other humoral defects, substitution therapy with immunoglobulins is the basis for treating the overall variable immune deficiency. However, in most cases it does not prevent all infectious problems, in this regard, many patients require preventive antibacterial therapy. In the treatment of granulomatous disease, corticosteroids are used. In the therapy of autoimmune and tumor pathology, protocols appropriate to the disease are used. Transplantation of hematopoietic stem cells with a general variable immune deficiency is not carried out.

Forecast

When carrying out substitution and antibacterial therapy, the average age of mortality in patients with a general variable immune deficiency, according to one of the studies, is 42 years. The main cause of death is tumors and chronic lung diseases.

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