Symptoms of combined T and B-cell immunodeficiencies

In humans, severe combined immunodeficiency was first described in 1950 in Switzerland in several infants with lymphopenia who died of infections during the first year of life. That is why the expression "Swiss type of SCID" was encountered in the literature for many years. In subsequent years, it was revealed that severe combined immunodeficiency includes many syndromes with different genetic origins and different types of inheritance (X-linked in 46% of cases and autosomal recessive in 54%). The overall incidence of SCID is 1:50,000 newborns. Currently, the genetic origin of approximately 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. Patients with SCID are characterized by early, in the first weeks and months of life, onset of clinical manifestations of the disease in the form of lymphoid tissue hypoplasia, persistent diarrhea, malabsorption, skin and mucous membrane infections, progressive damage to the respiratory tract. The causative agents of infections are bacteria, viruses, fungi, opportunistic microorganisms (primarily Pneumocyctis carini). Cytomegalovirus infection occurs in the form of interstitial pneumonia, hepatitis, enteroviruses and adenovirus cause meningoencephalitis. Candidiasis of the mucous membranes and skin, onychomycosis are very common. The development of regional and / or generalized BCG infection after vaccination is typical. Against the background of severe infections, a lag in physical and motor development is observed. It should be remembered that even in the presence of severe combined immunodeficiency, infants do not immediately develop all the above symptoms, and for 2-3 months they can grow and develop almost normally, especially if BCG vaccination has not been done. Transplacental transfer of maternal lymphocytes can cause symptoms of graft-versus-host disease (GVHD), in this case called maternal-fetal GVHD. It manifests itself mainly in the form of cutaneous erythematous or papular rash and liver damage.

Laboratory examination in most cases reveals severe lymphopenia, hypogammaglobulinemia and decreased proliferative activity of lymphocytes. A near-normal lymphocyte count may be the result of transplacental transfer 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 functions of B lymphocytes and NK cells depend on the genetic defect underlying SCID. In rare cases, normal immunoglobulin concentrations are observed, but their inadequate specificity leads to complete ineffectiveness of the humoral link. Below, 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 precursors at early stages of development in the bone marrow. Autosomal recessive inheritance is assumed, but due to the rarity of the disease, it has not been proven. The molecular genetic basis of the disease is unknown. 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 immunodeficiency

X-linked SCID, or g chain deficiency, is the most common form (more than 50% of all forms of severe combined immunodeficiency). It develops as a result of a mutation in the gene of the common g chain (CD132) of the receptors of interleukins 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 developing 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.

• Jak3 deficiency

The Janus family tyrosine kinase Jak3 is required to transmit the activation signal from the common chain of IL2, 4, 7, 9, 15 to the cell nucleus. Deficiency of jak3 causes the same profound impairment of T- and NK-cell differentiation as deficiency of the common chain. Immunological abnormalities and clinical manifestations in patients with Jak3 deficiency are similar to those in X-linked SCID.

• CD45 deficiency

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

T- B- NK+ TKIN

• Complete RAG1/RAG2 deficiency

Protein products of recombination activating genes (RAG1 and RAG2) initiate the formation of immunoglobulins and T-cell receptors necessary for differentiation of B and T cells. Thus, mutations of RAG genes lead to the formation of severe combined immunodeficiency. In this form of immunodeficiency, T and B cells are absent, while the number of NK cells is normal. The amount of serum immunoglobulins is sharply reduced.

• Radiosensitive SCID (Artemis deficiency)

In 1998, patients with T-B-NK+ severe combined immunodeficiency without RAG1/RAG gene mutations, highly sensitive to ionizing radiation, and impaired DNA double strand break repair were identified. T- and B-lymphocytes recognize antigens using T-cell receptor (TCR) molecules and immunoglobulinose. The antigen-specific regions of these receptors consist of three segments: V (variable), D (diversity), and J (unification). Polymorphism of the antigen-specific regions of TCR and immunoglobulins is provided by the process of somatic rearrangement and V(D)J recombination. During the recombination of immunoglobulin genes and TCR, RAG proteins induce double-strand DNA breaks. Repair of radiation-induced and spontaneous DNA breaks requires a number of protein kinases and a recently identified factor called Artemis. Artemis is required for cell cycle arrest in the event of DNA damage.

Mutations in the Artemis gene result in the development of autosomal recessive severe combined immunodeficiency 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 nomo-like lesions of the oral mucosa and other localizations.

T- B+ NK+ TKИH

• IL-7R deficiency

T- and B-cell precursors express a functional IL7R consisting of an a chain and a common y chain. Expression of this receptor is critical for T-lymphocyte maturation but not for B-lymphocyte development. Mutations in the IL-7R alpha chain gene result in SCID, with a TB-NK+ phenotype and markedly reduced serum immunoglobulin concentrations.

T+ B+ NK- TKIN

In 2001, Gilmour KC et al. first described a patient with low absolute T-lymphocyte counts, normal B-cell counts, and complete absence of NK cells. Although no mutations were found in the common Y chain or JAK3 genes, functional studies showed impaired phosphorylation of JAK3 via the IL2R complex. Subsequent flow cytometric analysis showed a significant decrease in expression of the IL15 receptor beta chain (IL15Rbeta). However, no mutations in the IL15Rbeta gene were detected, suggesting the presence of transcriptional defects that were responsible for the lack of IL15Rbeta chain expression.

• Purine metabolism enzyme deficiency

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 accumulate - deoxyadenosine and deoxyguanosine, which are partially phosphorylated in lymphoid cells, turning into the corresponding deoxynucleoside triphosphates. The toxicity of these products is especially important in rapidly dividing cells and consists of inhibition of DNA synthesis, induction of apoptosis, disruption of methylation, etc. Both of these conditions are heterogeneous in clinical manifestations depending on the localization of the mutation along the genes and the extent to which the function of the corresponding enzyme suffers as a result.

• Adenosine deaminase deficiency (ADA)

Adenosine deaminase deficiency is one of the first identified forms of SCID. The adenosine deaminase gene is located on 20ql3.ll. More than 50 mutations of the ADA gene are known. There is a relationship between genetically determined residual adenosine deaminase activity and the metabolic and clinical phenotype. ADA is expressed in various tissues, its expression is especially high in immature thymocytes and B lymphocytes, with ADA expression decreasing as the cells mature. In adenosine deaminase deficiency, deoxyadenosine triphosphate and S-adenosylhomocysteine accumulate in the cells. These metabolites inhibit the proliferation of TT and B lymphocytes.

Most patients with adenosine deaminase deficiency exhibit all the features of SCID at an early age. These are usually the patients with the lowest lymphocyte counts and the earliest and most severe manifestations. These patients do not show engraftment of maternal lymphocytes. In addition to immunological ones, purine metabolism disorders can cause skeletal disorders. Thus, X-ray examination reveals enlarged costochondral joints (as in rickets), widened rib ends, pelvic dysplasia. The following neurological changes have also been described in patients: nystagmus, sensory deafness, spastic disorders, impaired psychomotor development (independent of infections). A common sign of adenosine deaminase deficiency is an increase in transaminases, probably indicating the presence of toxic hepatitis.

In recent years, “late-onset” variants of ADA deficiency have been described, and even healthy individuals with partial enzyme deficiency have been identified.

Management of patients with severe manifestations of ADA deficiency is practically no different from the therapy of other SCID. However, an experimental method is the administration of substitution therapy with the enzyme PEG-ADA intramuscularly at a dose of 15-30 mg/kg/week. Correction of defects requires long-term and continuous treatment. The number and function of T lymphocytes usually improves by 6-12 weeks of therapy, but even after long-term treatment (10 years), lymphopenia and impaired mitogenic response persist in most patients.

• Purine nucleotide phosphorylase (PNP) deficiency

The PNP gene is located on 14ql3. Unlike ADA, purine nucleose phosphorylase activity increases as T lymphocytes mature. With PNP deficiency, deoxyguanosine triphosphate accumulates in cells, inhibiting T lymphocyte proliferation.

As with adenosine deaminase deficiency, most patients with purine nucleose phosphorylase deficiency develop clinical manifestations of SCID in infancy, although in some cases a later onset has been described. Associated syndromes with PNP deficiency are uricemia and uricuria. Patients with purine nucleose phosphorylase deficiency often have autoimmune (hemolytic anemia, thrombocytopenia, neutrolenia, systemic lupus erythematosus) and neurological (plegia, paresis, ataxia, tremor, mental retardation) manifestations. Patients have an increased tendency to cancer. Laboratory tests show a sharp decrease in T lymphocytes and, as a rule, a normal number of B lymphocytes. Manifestations of B lymphocyte dysregulation include increased levels of immunoglobulins, gammopathy, and the presence of autoantibodies.

• MHC II deficiency

Naked lymphocyte syndrome is a congenital immunodeficiency that develops due to the absence of expression of class II molecules of the major histocompatibility complex (MHC II) on the cell surface. In this disease, due to defects in the genes controlling MHC II, there is no expression of its molecules necessary for differentiation and activation of CD4+ cells, T-cell selection in the thymus is impaired, and severe immunodeficiency develops. Damaged genes encode four highly specific transcription factors (RFXANK, RFX5, RFXAP and CITA) that regulate MHC II expression. 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-DNA-binding co-activator that controls MHC II expression.

The disease is characterized by typical clinical signs of SCID, which, however, are milder. Thus, in a group of 9 non-transplanted patients with this disease, the average life expectancy was 7 years.

Laboratory examination reveals a significant decrease in CD4+ lymphocytes, with a generally normal number of CD8+ lymphocytes. Some patients show a lack of expression of not only MHC II molecules, but also MHC I. In general, there is a pronounced deficiency of the T cell response, and immunoglobulin production is also sharply reduced.

• TAP deficiency

TAP (Transporter Associated Protein) is required for transport of antigen peptides into the endoplasmic reticulum and their attachment to class I MHC molecules. Defects of TAP subunits 1 and 2 (TAP1 and TAP2) have been identified. Characteristic laboratory manifestations in patients with TAP deficiency are: lack of class I MHC expression, near-normal immunoglobulin levels (selective IgM deficiency was noted in some patients), and lack of antibody response to polysaccharide antigens. Various patients had normal or progressively decreasing CD8 T lymphocyte counts, while other lymphocyte subpopulations were usually normal. This form of CIN is associated with high susceptibility to bacterial infections of the respiratory tract mucosa, and granulomatous skin lesions are characteristic. Viral infections and infections caused by intracellular pathogens are rare. Asymptomatic course and late onset of clinical manifestations of immunodeficiency have been described in some patients.

• CD25 deficiency

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

• Deficiency of SVZ 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 consisting of two peptide chains - ab and yv. The main function of TCR is to bind an antigen peptide associated with the products of the major histocompatibility complex, and CD3 is to transmit an antigen signal to the cell. CD3 includes molecules of 4-5 types. All chains of the CD3 complex (y, v, e, £, t) are transmembrane proteins. Mutations in the genes of the y, v or £ chains lead to a decrease in the number of mature T cells with low TCR expression. Mutations in the e chain gene lead to a violation of thymocyte differentiation at the CD4-CD8- level. In humans, CD3 deficiency results in a decrease in CD8+ T lymphocytes and CD4+CD45RA+, the content of CD4+CD45R0+, B and NK cells and serum immunoglobulin concentrations are normal. The clinical phenotype in CD3y and CD3e deficiency varies even among members of the same family from manifestations to a rather mild course of the disease.

• ZAP70 deficiency

Protein tyrosine kinases of the ZAP70/Syk family play an important role in signal transduction from the antigen-recognizing receptor and are necessary for normal T-lymphocyte development. ZAP70 is necessary for ab T-lymphocyte differentiation. ZAP70 deficiency results in a selective deficiency of CD8+ cells. The number of circulating CD4+ cells is normal, but they have significant functional impairments in the form of a lack of IL-2 production and proliferative activity. Serum immunoglobulin concentrations are reduced.