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ZAP-70 deficiency

ZAP-70 deficiency
Literature review current through: May 2024.
This topic last updated: Nov 30, 2023.

INTRODUCTION — The zeta chain-associated protein kinase of 70 kD (ZAP-70) is involved in T cell receptor (TCR) signaling and is critical for T cell differentiation and function. Deficiency of ZAP-70 causes a combined immunodeficiency (CID). Affected children present within the first two years of life with a history of recurrent infections, similar to infants with severe combined immunodeficiency (SCID). However, diagnosis can be delayed because most patients with ZAP-70 deficiency have detectable lymphoid tissues and a normal lymphocyte count. The treatment of choice is hematopoietic cell transplantation (HCT).

A review of ZAP-70 deficiency (MIM +176947) is discussed here. Reviews related to other CIDs are presented separately. SCID disorders are also discussed separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency" and "Combined immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

TCR genetics, structure, biology, and signaling are covered in detail separately as well. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation' and "The adaptive cellular immune response: T cells and cytokines", section on 'T cell activation and functions' and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology' and "T cell receptor signaling".)

BRIEF OVERVIEW OF T CELL RECEPTOR SIGNALING — T cell receptor (TCR) signaling in naïve T cells is initiated by binding of TCR to a peptide-major histocompatibility (MHC) complex expressed on the surface of antigen-presenting cells (figure 1 and figure 2). This association leads to activation of multiple pathways, eventually culminating in a T cell response. The Src-family protein tyrosine kinase Lck is first activated with resultant phosphorylation of motifs known as immune receptor tyrosine-based activation motifs (ITAMs). Phosphorylated ITAMs on CD3 zeta serve as binding sites for ZAP-70. ZAP-70 is also activated by autophosphorylation. The role of this kinase in TCR signaling was unveiled by studying humans with ZAP-70 deficiency. Activated ZAP-70 phosphorylates a variety of downstream molecules, resulting in calcium mobilization, actin cytoskeleton rearrangement, and activation of Ras guanosine triphosphate hydrolase (GTPase). These events lead to activation of several transcription factors with resultant T cell proliferation and differentiation. (See "T cell receptor signaling".)

EPIDEMIOLOGY — ZAP-70 deficiency is a rare combined immunodeficiency (CID) with an autosomal recessive pattern of inheritance. The disease was first described in 1989 in a patient of Mennonite descent with CD8 lymphocytopenia [1]. Pathogenic variants in ZAP-70 were initially identified in Mennonite kindreds and subsequently in other ethnicities including Hispanic, Japanese, Turkish, White, Portuguese, Indian, Iranian, and Chinese patients [2-11].

PATHOGENESIS — ZAP-70 plays a crucial role in T cell development and function, although the exact mechanisms are not fully understood [12,13]. The thymus is not dysplastic in patients with ZAP-70 deficiency, unlike typical cases of combined immunodeficiency (CID) or severe combined immunodeficiency (SCID). Thymus architecture and cellularity are preserved, as are the number and size of Hassall's corpuscles. Normal expression of CD3/CD4/CD8 double-positive thymocytes in the cortex and single positive CD3/CD4, but not CD8 T cells, are present in the medullary area as seen on immunohistochemistry.

The phenotype of affected patients suggests that ZAP-70 is critical for CD8 T cell selection and peripheral CD4 and CD8 T cell function but is dispensable for CD4 selection in the thymus. One possible explanation for the presence of normal numbers of peripheral CD4+ T cells is that Syk, which is expressed at higher levels in the thymus than in the blood in humans, may rescue CD4 selection in the absence of ZAP-70 [14,15]. The differential ability of Syk to replace ZAP-70 in CD4 versus CD8 selection events may be related to the preferential association of Lck with the CD4 coreceptor. This preferential association would facilitate CD4 selection if Syk was unable to fully substitute for loss of ZAP-70 function during thymocyte differentiation. Normal downregulation of Syk activity in mature T cells would abrogate T cell receptor (TCR) signaling altogether and lead to combined CD4 and CD8 immunodeficiency in patients with ZAP-70 deficiency, but studies so far have been controversial [14-18].

Other studies suggest that ZAP-70 may affect thymopoiesis at an earlier stage than previously considered. Assessment of gene rearrangement events that represent sequential stages of thymocyte maturation suggest a reduction, but not a complete block, of T cell development during transition from double-negative to double-positive cells [19]. This may explain the low levels of T cell receptor excision circles (TRECs) found in peripheral CD4+ cells, consistent with a relatively low number of naïve cells. However, this model cannot explain the preferential selection of single-positive CD4+ T cells. The expansion and survival of CD4+ T cells in the circulation may be explained by their reduced ability to undergo apoptosis [19].

ZAP-70 is also critical for T cell function. Peripheral T cells from ZAP-70-deficient patients demonstrate defective TCR-mediated signaling, but they are capable of secreting interleukin (IL) 2 and proliferating if stimulated with phorbol myristate acetate (PMA) and ionomycin that bypass the need for early TCR-mediated events [2,4,5]. These T cells are polyclonal, with full representation of the TCR repertoire, although CD4 cells do not differentiate into T helper 2 (Th2) cells and lack inhibitory controls, such as IL-10 and tumor necrosis factor (TNF) beta [19]. This phenotype has the hallmarks of an autoimmune signature. Indeed, several patients have presented with overt autoimmune disorders.

GENETICS — ZAP-70 deficiency is due to autosomal recessive pathogenic variants in the ZAP70 gene, located on chromosome 2q12 [5]. Several separate variants in the ZAP70 gene have been identified [2,4-6,16-18,20,21]. Most variants occur within the kinase domain of the ZAP-70 protein and significantly affect both protein stability and catalytic activity (figure 3). There is one report of a variant leading to expression of ZAP-70 that is rapidly degraded [22] and another report of a defect that results in an expressed but nonfunctional protein [16]. One hypomorphic variant in a noncoding intron resulting in decreased protein expression and a milder phenotype has been described [23]. In addition, a family with two siblings who were compound heterozygous for both a hypomorphic variant in the first Src-homology 2 (SH2) domain and an activating variant in the kinase domain had a unique constellation of autoimmune phenotypes including bullous pemphigoid associated with autoantibodies [21].

CLINICAL MANIFESTATIONS — Some children with ZAP-70 deficiency present within the first two years of life with a history of recurrent infections, similar to infants with severe combined immunodeficiency (SCID). However, unlike those patients, ZAP-70 deficiency patients may present later in childhood and invariably have palpable lymph nodes, visible tonsils, and a thymus shadow on imaging (image 1) [3]. (See "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies: An overview".)

Other findings are also somewhat different in patients with ZAP-70 deficiency than in infants with SCID. Pneumocystis jirovecii (formerly carinii), pneumonia, and cytomegalovirus (CMV) pneumonitis are less common. These infections may appear later than six months of age, and, at least initially, they respond well to antibiotic or antiviral treatment. Similarly, chronic diarrhea and failure to thrive are less frequent and appear in less than half of the patients reported.

Autoimmunity or manifestations of immune dysregulation such as ulcerative colitis and blood cytopenias are reported [24]. Unique presentations such as pustular skin lesions from birth, subcutaneous nodules [6], lymphoma [20], and multisystem autoantibody disease [21] are also seen. In one family with a unique pathogenic variant profile, two children had bullous pemphigoid, nephrotic syndrome, autoimmune hemophilia, and inflammatory bowel disease [21]. In addition, cases with aberrant inflammatory features like Omenn syndrome and hemophagocytic lymphohistiocytosis (HLH) have been described [7]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis" and "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype'.)

LABORATORY FINDINGS — Patients with ZAP-70 deficiency have normal to elevated numbers of circulating lymphocytes (range: 4000 to 20,000 x cells/microliter) [2,4-6,16-18,20], in contrast to the lymphopenia seen in patients with severe combined immunodeficiency (SCID) or other forms of combined immunodeficiency (CID).

Phenotypic analysis of ZAP-70-deficient peripheral blood lymphocytes reveals normal to increased percentages of CD3 (38 to 80 percent) and CD4 (37 to 75 percent) T cells due to the lack of CD8 T cells (0 to 5 percent) [2,4,5]. Expression of T cell surface proteins other than CD8 is normal. ZAP-70-deficient peripheral T cells are polyclonal and not maternal in origin by molecular analysis [2,19]. Natural killer (NK) cell numbers (1 to 10 percent) and activity (20 to 30 percent) are relatively normal [25]. All patients have normal B cell numbers (13 to 41 percent) [2,4,5]. Thymic histology is remarkable for normal architecture, including normal corticomedullary demarcation and the presence of Hassall's corpuscles. Immunohistochemistry shows preserved expression of CD4 on T cells in both the cortex and medullary areas but selective expression of CD8 on T cells in the cortex only and not the medulla [2,3].

T cell function — Absent T cell proliferative responses to mitogens in vitro, including phytohemagglutinin (PHA) and anti-CD3 (CD3 monoclonal antibody), are seen, as is anergy to candidal skin testing [3-5]. Failure to reject an allogeneic skin graft was also demonstrated in one patient [3].

B cell function — Serum immunoglobulin G (IgG) may be normal or reduced, while immunoglobulin M (IgM) and immunoglobulin A (IgA) levels are normal [2-5]. Specific antibody production is variable, with some patients having tetanus antibodies or specific immunoglobulin E (IgE) antibodies against allergens [18].

Signaling defects — Critical defects within the proximal T cell receptor (TCR) signaling pathway are seen in ZAP-70-deficient T cells. Affected T cells exhibit diminished or absent changes in intracellular calcium ([Ca2+]i) mobilization [2,4,5] and poor induction of most cytoplasmic tyrosine phosphoproteins after TCR stimulation [2,4,5]. ZAP-70-deficient lymphocytes proliferate normally to phorbol myristic acetate (PMA) plus ionomycin, a combination of agents that bypasses proximal TCR signaling events by mimicking actions of the second messengers diacylglycerol and [Ca2+]i [2,4,5]. In addition, interleukin (IL) 2 production is normal when lymphocytes are stimulated with PMA plus ionomycin but absent when T cells are stimulated through the TCR [2,17,25].

DIAGNOSIS — The presentation of ZAP-70 can pose a diagnostic challenge. ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial or opportunistic infections in spite of having palpable lymph nodes, notable thymus shadow, and normal lymphocyte count. It should also be suspected in patients with early-onset autoimmunity and lymphoma. The initial evaluation should include enumeration of peripheral blood T cell subsets and B cells, serum immunoglobulin, and T cell responses to mitogens in vitro.

The diagnosis is suggested by the presence of relatively normal numbers of peripheral blood lymphocytes (>3.5 x 109/L) and normal or only modestly decreased total T cells (>1.2 x 109/L) but absent CD8 T cells (<5 percent) in the circulation. Analysis of T cell receptor excision circles (TRECs) may also be valuable since these levels appear to gradually decline during the first year of life in patients with ZAP-70 deficiency [19,26]. Absent T cell proliferation to T cell receptor (TCR) mediated stimuli, such as phytohemagglutinin (PHA), CD3 monoclonal antibody, or to alloantigen in mixed lymphocyte culture, confirms the diagnosis of a cellular immunodeficiency.

The patient most likely has ZAP-70 deficiency if further evaluation demonstrates that in vitro T cell proliferation to PMA plus ionomycin (which bypass the need for early signaling) is comparable with that of normal T cells. Protein expression by immunoblot may help in diagnosis if ZAP-70 is absent or reduced. Complementary deoxyribonucleic acid (cDNA) or genomic DNA sequencing to identify pathogenic variants in the ZAP70 gene confirms the diagnosis.

Newborn screening based upon quantification of the number of TRECs cannot be relied upon to detect ZAP-70 deficiency, because TREC levels are normal in newborns with this immunodeficiency [19,27], although they decline over time [26]. The defect in TCR signaling in ZAP-70 deficiency occurs after the developmental stage of T cell rearrangement, which is the process that generates TRECs. (See "Newborn screening for inborn errors of immunity", section on 'Diseases identified by TREC testing'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes other profound immunodeficiencies that present with normal numbers of circulating lymphocytes and CD8 lymphocytopenia (see "Combined immunodeficiencies: An overview" and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology' and "Severe combined immunodeficiency (SCID): Specific defects" and "Severe combined immunodeficiency (SCID): An overview"):

Omenn syndrome – This condition is associated with pathogenic variants in any of several genes associated with severe combined immunodeficiency (SCID), most commonly recombination-activating gene 1 (RAG1) or recombination-activating gene 2 (RAG2). Unlike ZAP-70 deficiency, these patients present with erythroderma, patchy alopecia, and lymphadenopathy, as well as an increased eosinophil count and increased IgE levels. Assessment of T cell repertoire frequently shows oligoclonality. In some cases of Omenn syndrome, only the CD4 T cell compartment is expanded, therefore mimicking the CD8 T cell lymphopenia of ZAP-70 deficiency.

Human leukocyte antigen (HLA) class I deficiency – Like ZAP-70 deficiency, these patients present with CD8 lymphopenia but normal CD4 T cells, B cells, and serum immunoglobulins. Unlike ZAP-70 deficiency, these patients lack the expression of HLA class I molecules on the surface of lymphocytes. They generally present at a later age (second or third decade of life) with chronic sinusitis, chronic lung disease, and vasculitis.

CD8 alpha deficiency – These patients present with CD8 lymphocytopenia and normal CD4 T cells in the second or third decade with sinopulmonary infections. The ZAP-70 gene is normal, but pathogenic variants in the CD8 alpha gene are found in these patients.

TREATMENT — The general management of patients with a primary combined immunodeficiency (CID), including infection avoidance; vaccination with killed, but not live, vaccines; antibiotic prophylaxis; cytomegalovirus (CMV) negative, leuko-reduced, irradiated blood products; and immune globulin replacement, is discussed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Patients with ZAP-70 deficiency require hematopoietic cell transplantation (HCT) to cure their CID [2,4,5,7,16]. Conditioning with busulfan and cyclophosphamide with or without antithymocyte globulin is commonly done prior to HCT. Bone marrow from a human leukocyte antigen (HLA) matched sibling is the optimal choice, with excellent survival, as well as long-term immune reconstitution [28]. However, most patients lack this option. In such situations, other histocompatible donors can be used, although careful assessment of long-term survival and immune reconstitution is scarce [8]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Preparative regimens for hematopoietic cell transplantation" and "Immune globulin therapy in inborn errors of immunity".)

Gene therapy has not been attempted yet for ZAP-70 deficiency, although preliminary in vitro studies in human cells [29,30] and studies in murine models [31,32] have been performed.

PROGNOSIS — Most patients with ZAP-70 deficiency die within the first two years of life from infection if they do not undergo hematopoietic cell transplantation (HCT).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

Pathogenesis – Zeta chain-associated 70 kDa protein kinase (ZAP-70) is a signaling molecule associated with the T cell receptor (TCR) complex (figure 2) that is primarily expressed in T cells and in natural killer (NK) cells. It is required for normal human T cell development and function. Deficiency of ZAP-70 results in a combined immunodeficiency (CID) (figure 1) that is characterized by the selective absence of circulating CD8+ T cells and by abundant CD4+ T cells in the peripheral blood that are unresponsive to TCR-mediated stimuli in vitro. (See 'Pathogenesis' above.)

Genetics – ZAP-70 deficiency is due to pathogenic variants in the ZAP70 gene, located on chromosome 2q12. Most variants occur within the kinase domain of the ZAP-70 protein and significantly affect both protein stability and catalytic activity (figure 3), although a novel activating variant leads to severe autoantibody-mediated disease. (See 'Genetics' above.)

Clinical manifestations – Affected children present within the first two years of life with a history of recurrent infections and sometimes also chronic diarrhea and/or failure to thrive, similar to, but at a somewhat later age than, severe combined immunodeficiency (SCID). Alternative presentations include pustular skin manifestations, autoimmune features with bullous pemphigoid in one family, Omenn syndrome, hemophagocytic lymphohistiocytosis (HLH), or lymphoma. (See 'Clinical manifestations' above.)

Laboratory findings – Patients with ZAP-70 deficiency have normal-to-elevated numbers of circulating lymphocytes. The total T cell number is normal or only modestly decreased, but CD8 T cells are absent (<5 percent) in the circulation. T cell receptor excision circle (TREC) levels in ZAP-70-deficient cells may be normal or low, indicating that they may be missed by TREC newborn screening. (See 'Laboratory findings' above and 'Diagnosis' above.)

Diagnosis and differential diagnosis – The diagnosis is suggested by the presence of relatively normal numbers of peripheral blood lymphocytes (>3.5 x 109/L) and normal or only modestly decreased total T cells (>1.2 x 109/L) but absent CD8 T cells (<5 percent) in the circulation. cDNA or genomic DNA sequencing to identify pathogenic variants in the ZAP70 gene confirms the diagnosis. The presence of lymphopenia suggests an alternative diagnosis. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Treatment – Hematopoietic cell transplantation (HCT) is the only curative therapy available for ZAP-70 deficiency. (See 'Treatment' above and 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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