Symptoms of combined T and B-cell immunodeficiency

In humans, severe combined immune deficiency was first described in 1950 in Switzerland in several infants with lymphopenia, dying from infections during the first year of life. That is why for many years in the literature there was the expression "Swiss type TKIN". In subsequent years, it was found that severe combined immune deficiency includes a variety of syndromes that are of different genetic nature and different types of inheritance (X-linked in 46% of cases and autosomal recessive in 54%). The overall frequency of SCID is 1:50 000 newborns. At present, the genetic nature of about 15 forms of SCID is known, which, based on differences in the immunological phenotype, can be divided into 5 groups: T-B + NK +, TB-NK +, T-B + NK-, T + B + NK- and T -B-NK-.

The main clinical manifestations of severe combined immune deficiency are practically independent of the genetic defect. For patients with SCI is characterized by early, in the first weeks and months of life, the onset of clinical manifestations of the disease in the form of hypoplasia of lymphoid tissue, persistent diarrhea, malabsorption, infections of the skin and mucous membranes, progressive defeat of the respiratory tract. Infectious agents are bacteria, viruses, fungi, opportunistic microorganisms (primarily Pneumocyctis carini). Cytomegalovirus infection occurs in the form of interstitial pneumonia, hepatitis, enteroviruses and adenovirus cause meningoencephalitis. Very part is found in candidiasis of mucous membranes and skin, onychomycosis. Characteristic is the development of regional and / or generalized BCG infection after vaccination. Against the backdrop of severe infections, there is a backlog in physical and motor development. It should be remembered that even in the presence of severe combined immune deficiency, all the above symptoms do not immediately develop in babies, and within 2-3 months they can grow and develop almost normally, especially if BCG vaccination was not done. Transplacental transfer of maternal lymphocytes can cause symptoms of a "graft versus host" (GVHD) reaction, called a maternal-fetal GVHD in this case. It manifests itself mainly as a cutaneous erythematous or papular rash and liver damage.

In laboratory examination, in most cases, marked lymphopenia, hypogammaglobulinemia and a decrease in the proliferative activity of lymphocytes. A close to normal number of lymphocytes may be the result of transplacental transmission of lymphocytes from the mother. As noted above, T-lymphocytes are significantly reduced in all forms of severe combined immune deficiency, but the number and function of B lymphocytes and NK cells depends on the genetic defect underlying SCID. In rare cases, a normal concentration of immunoglobulins is noted, but their inadequate specificity leads to complete ineffectiveness of the humoral link. Next, we will consider some features of the pathogenesis of various forms of severe combined immune deficiency.

Molecular genetic features of various forms of severe combined immune deficiency

T- B- NK-TKIN

• Reticular dysgenesis

Reticular dysgenesis is a rare form of severe combined immune deficiency characterized by impaired maturation of lymphoid and myeloid progenitors in the early stages of development in the bone marrow. Autosomal recessive inheritance is presumed, but due to the rarity of the disease it is not proven. Molecular genetic basis of the disease is not known. The disease is characterized by severe lymphopenia, granulocytopenia, thrombocytopenia, severe infections leading to early death of patients.

T- B + NK-TKIN

• X-linked severe combined immune deficiency

X-linked TKIN, or g-deficiency is the most common form (more than 50% of all forms of severe combined immune deficiency). It develops as a result of mutation of the gene common in the chain (CD132) of the interleukin receptors 2, 4, 7, 9, 15. The mutation in the chain leads to blockade of the receptors, as a result of which the target cells are unable to respond to the action of the corresponding interleukins. Immunological disorders that develop in these patients are characterized by the absence of T cells and NK cells and an increase in the number of B cells. As a result of the lack of T-cell regulation, the production of immunoglobulins by B cells is sharply reduced.

• Deficiency of Jak3

The Janus-Jak3 family tyrosine kinase is required to transfer the activation signal from the total ligament of IL2, 4, 7, 9, 15 to the nucleus of the cell. Deficiency of jak3 causes the same deep violations of T- and NK-cell differentiation as a general cohosh deficiency. Immunological abnormalities and clinical manifestations in patients with Jak3 deficiency are similar to those in X-linked SCID.

• Deficiency CD45

Transmembrane protein tyrosine kinase CD45, specific for hematopoietic cells, is required for signal transmission from the antigenic T- and B-cell receptor. Mutations of the CD45 gene lead to the development of SCID characterized by a sharp decrease in the number of T cells, normal B cell content, and a progressive decrease in serum immunoglobulin concentrations. The number of NK lymphocytes is reduced, but not completely.

T- B- NK + TKIN

• Total deficiency of RAG1 / RAG2

The protein products of recombination activating genes (RAG1 and RAG2) initiate the formation of immunoglobulins and T-cell receptors necessary for the differentiation of B- and T-cells. Thus, mutations of RAG genes lead to the formation of severe combined immune deficiency. With this form of immunodeficiency, there are no T and B cells, while the number of NK cells is normal. The amount of serum immunoglobulins is sharply reduced.

• Radiosensitive TKIN (Artemis deficiency)

In 1998, patients with T-B-NK + severe combined immune deficiency without mutations of RAG1 / RAG genes were identified, characterized by high sensitivity to ionizing radiation and having a disruption of DNA double strand break repair, T- and B lymphocytes recognize antigens using T-cell receptor molecules (TCRs) and immunoglobulins. The antigen-specific regions of these receptors consist of three segments: V- (variable), D (variety) and J (pooling). Polymorphism of antigen-specific regions of TCR and immunoglobulins is provided by the process of somatic re-arangement and V (D) J recombination. In the process of recombination of immunoglobulin and TCR RAG genes, proteins induce double-stranded DNA breaks. Restoration of radiation induced and spontaneous DNA breaks requires the participation of a number of protein kinases and a newly identified factor called Artemis. Artemis is required to stop the cell cycle in the event of DNA damage.

Mutations of the Artemis gene lead to the development of autosomal recessive severe combined immune deficiency with increased radiosensitivity, characterized by the absence of T and B lymphocytes and chromosomal instability. A distinctive feature of clinical manifestations, in addition to those characteristic of scex SCID, is the presence of nome-like lesions of the oral mucosa and other localizations.

T- B + NK + TKHH

• Deficiency of IL-7R

The T- and B-cell progenitors express functional IL7R consisting of a chain and a common chain. Expression of this receptor is critical for the maturation of T-lymphocytes, but not critical for the development of B-lymphocytes. Mutations of the alpha-IL-7R gene lead to the development of SCID, with the phenotype of TB-NK + and a marked decrease in serum concentrations; immunoglobulins.

T + B + NK-TKIN

In 2001, for the first time, Gilmour KC et al. Described a patient with a low absolute number of T-lymphocytes, a normal number of B cells, and a complete absence of NK cells. Although no mutations were found in the genes common to the chain or JAK3, functional studies showed a disruption of the phosphorylation of JAK3 through the IL2R complex. Subsequent cytometric analysis showed a significant decrease in the expression of the beta chain of the IL15 receptor (IL15Rbeta). However, mutations of the IL15Rbeta gene could not be detected, suggesting that transcription defects were present that were responsible for the absence of IL15Rbeta chain expression.

• Deficiency of Purine Exchange Enzymes

The deficiency of two enzymes that catalyze purine metabolism - adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), is associated with the development of combined immune deficiency. Due to the absence of these enzymes, toxic products for cells - deoxyadenosine and deoxyguanosine - are accumulated, which are partially phosphorylated in lymphoid cells, turning into corresponding deoxynucleoside triphosphates. The toxicity of these products is particularly important in rapidly dividing cells and consists in inhibiting DNA synthesis, apoptosis induction, methylation disturbance, etc. Both these states are heterogeneous in clinical manifestations depending on the location of the mutation throughout genes, as much as the function of the corresponding enzyme suffers as a result.

• Deficiency of adenosine deaminase (ADA)

Deficiency of adenosine deaminase is one of the first identified forms of SCID. The gene adenosine deaminase is at 20ql3.ll. There are more than 50 variants of mutations of the ADA gene. There is a relationship between the genetically determined residual activity of adenosine deaminase and the metabolic and clinical phenotype. ADA is expressed in various tissues, especially its expression in immature thymocytes and in lymphocytes, as the cells mature, the expression of ADA decreases. With adenosine deaminase deficiency, deoxyadenosine triphosphate and S-adenosyl homocysteine accumulate in the cells. These metabolites inhibit the proliferation of TT and B lymphocytes.

In most patients with adenosine deaminase deficiency, all signs of SCID appear at an early age. This is usually a patient with the lowest number of lymphocytes and the earliest and most severe manifestations. These patients do not have an engraftment of maternal lymphocytes. In addition to immunological, violation of purine metabolism can cause skeletal disorders. Thus, with X-ray examination, enlarged bone-chondral joints (as in rickets), widening of the rib ends, pelvic dysplasia are revealed. Patients also described the following neurologic changes: nystagmus, sensory deafness, spastic disorders, impaired psychomotor development (regardless of infections). A frequent sign of adenosine deaminase deficiency is an increase in transaminases, probably indicative of the presence of toxic hepatitis.

In recent years, variants have been described with the "late onset" of ADA deficiency and even healthy individuals with partial deficiency of the enzyme are detected.

Management of patients with severe manifestations of ADA deficiency is practically the same as that of other SCIDs. However, the experimental method is the appointment of a substitution intramuscular therapy with PEG-ADA enzyme at a dose of 15-30 mg / kg / week. Correction of defects requires a long and constant treatment. The number and function of T lymphocytes generally improves to 6-12 weeks of therapy, but even after prolonged treatment (10 years), most patients retain lymphopenia and a mitogenic response.

• Purine-Nucleosond Phosphorylase Deficiency (PNP)

The PNP gene is located at 14ql3. In contrast to ADA, the purine nucleosynphosphorylase activity increases with the maturation of T lymphocytes. With deficiency of PNP in the cells, de-oxyguanosine triphosphate accumulates, which inhibits the proliferation of T-lymphocytes.

As with adenosine deaminase deficiency, in most patients with a purine-nucleosynphosphorylase deficiency, clinical manifestations of SCID develop in infancy, although in some cases a later onset is described. Concomitant syndromes with a deficiency of PNP are uricemia and uricuria. Often in patients with a deficiency of purine nucleosynphosphorylase, autoimmune (hemolytic anemia, thrombocytopenia, neutrophilia, systemic lupus erythematosus) and neurologic (plegia, paresis, ataxia, tremor, mental retardation) manifestations are noted. Patients with an increased tendency to cancer. In a laboratory study, there is a sharp decrease in T lymphocytes and, as a rule, a normal B lymphocyte count. The manifestation of dysregulation of B lymphocytes is an increase in the level of immunoglobulins, gammopathy, the presence of autoantibodies.

• Deficiency of MHC II

The syndrome of "bare lymphocytes" is a congenital immunodeficiency that develops due to the absence of expression on the surface of cells of class II molecules of the main histocompatibility complex (MHC II). In this disease, due to defects in genes controlling MHC II, there is no expression of its molecules necessary for the differentiation and activation of CD4 + cells, the selection of T cells in the thymus is disrupted, and severe immunodeficiency develops. Damaged genes encode four highly specific transcription factors (RFXANK, RFX5, RFXAP and SITA) regulating the expression of MHC II. The first three are subunits of RFX (Regulatory Factor X), a trimeric, DNA-binding complex that regulates all MHC II promoters. CIITA {Class II Trans activator) is a non-binding DNA co-activator that controls the expression of MHC II.

The disease is characterized by typical clinical signs of SCID, which, however, proceed more easily. Thus, in the group of 9 untransplanted patients with this disease, the average life expectancy was 7 years.

In a laboratory study, there was a significant decrease in CD4 + lymphocytes, with a normal normal CD8 + lymphocyte count. In some patients, there is no expression of not only MHC II molecules, but also MHC I. Overall, there is a pronounced insufficiency of the T cell response, production of immunoglobulins is also sharply reduced.

• TAP deficiency

TAP {Transporter Associated Protein) is required for the transport of antigenic peptides to the endolasomatic reticulum and their attachment to MHC class I molecules. Defects of 1 and 2 subunits of TAP (TAP1 and TAP2) were revealed. Typical laboratory manifestations in patients with TAP deficiency are: absence of MHC class I expression, close to normal levels of immunoglobulins (in some patients, a selective IgM deficiency is noted), absence of an antibody response to polysaccharide antigens. Different patients had a normal or progressively decreasing number of CD8 T lymphocytes, the remaining subpopulations of lymphocytes were usually normal. With this form of CIN, there is a high sensitivity to bacterial infections of the mucosal respiratory tract, granulomatous skin lesions are characteristic. Viral infections and infections caused by intracellular pathogens are rare. Individual patients described asymptomatic course and late onset of clinical manifestations of immunodeficiency.

• Deficiency CD25

Mutations of the IL-2 receptor IL-2 (IL2Rct) {CD25) gene lead to the development of CIN with a decrease in the number and a violation of proliferation of peripheral T cells and normal development of B cells. The differentiation of thymocytes is not disturbed, but despite normal expression of CD2, CD3, CD4 and CD8, CD25, cortical thymocytes do not express CD1. Patients have increased sensitivity to viral infections (CMV, etc.), also from an early age suffer repeated bacterial and fungal infections, chronic diarrhea. Patients also have lymphoproliferation similar to that of ALPS. It is assumed that it is based on a disorder in the regulation of apoptosis in the thymus, leading to the expansion of autoreactive clones in various tissues.

• Deficiency of CBZ and CD3e

The antigen-recognizing receptor complex of T cells consists of the T cell receptor (TCR) itself and the CD3 molecule. There are two types of TCR, each of which consists of two peptide chains - ab and yv. The main function of TCR is the binding of the antigenic peptide associated with the products of the major histocompatibility complex, and CD3 is the transfer of the antigen signal to the cell. CD3 includes molecules of 4-5 types. All chains of the complex CD3 (y, v, e, £, t) are transmembrane proteins. Mutations in the gene chains y, v, or £ lead to a decrease in the number of mature T cells with low TCR expression. Mutations of the e gene of the chain lead to a violation of thymocyte differentiation at the level of CD4-CD8-. In humans, the deficiency of CD3 y leads to a decrease in the number of CD8 + T-lymphocytes and CD4 + CD45RA +, CD4 + CD45R0 +, B- and NK-cells and serum immunoglobulin concentrations are normal. The clinical phenotype with deficiency of CD3y and CD3e varies even among members of one family from manifestations to a fairly mild course of the disease.

• Deficiency ZAP70

Protein tyrosine kinases of the ZAP70 / Syk family play an important role in signal transmission from the antigen-recognizing receptor, they are necessary for the normal development of T-lymphocytes. ZAP70 is necessary for differentiation of ab T lymphocytes. With a deficiency of ZAP70, selective deficiency of CD8 + cells develops. The number of CD4 + circulating cells is normal, but they have pronounced impairments in the form of a lack of IL-2 production and proliferative activity. Concentrations of serum immunoglobulins are reduced.