Primary Combined Antibody and Cellular Immunodeficiencies

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Chapter 120 Primary Combined Antibody and Cellular Immunodeficiencies

Rebecca H. Buckley

Patients with combined antibody and cellular defects have severe, frequently opportunistic infections that lead to death in infancy or childhood unless they are provided hematopoietic stem cell transplantation early in life. These are thought to be rare defects, although the true incidences are unknown because there has been no newborn screening for any of these defects. It is possible that many affected children die of infection during infancy without being diagnosed. The defective gene products for many combined immunodeficiencies are identified (Table 120-1). Because life threatening infection may occur in infancy, screening for SCID has been recommended by the U.S. Secretary of Health and Human Services to be included in the state newborn screening programs. Live, vaccine-derived infections have occurred during this time of life and knowledge of SCID status could prevent these infections. In addition, early identification and subsequent bone marrow transplantation before life-threatening infections and end organ injury is the best approach to therapy.

Table 120-1 GENETIC BASIS OF COMBINED IMMUNODEFICIENCY DISORDERS

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120.1 Severe Combined Immunodeficiency (SCID)

Rebecca H. Buckley

The syndromes of SCID are caused by diverse genetic mutations that lead to absence of all adaptive immune function and, in some, a lack of natural killer (NK) cells. Patients with this group of disorders have the most severe immunodeficiency.

Pathogenesis

SCID results from mutations in any 1 of 13 known genes that encode components of the immune system crucial for lymphoid cell development (Table 120-2). All patients with SCID have very small thymuses (<1 g) that usually fail to descend from the neck, contain no thymocytes, and lack corticomedullary distinction or Hassall corpuscles. The thymic epithelium appears histologically normal. Both the follicular and paracortical areas of the spleen are depleted of lymphocytes. Lymph nodes, tonsils, adenoids, and Peyer patches are absent or extremely underdeveloped.

Table 120-2 PATHOPHYSIOLOGY MECHANISMS THAT ACCOUNT FOR SEVERE COMBINED IMMUNE DEFICIENCY (SCID)

DISEASE MECHANISM GENE DEFECTS
Increased apoptosis
• Due to mitochondrial energy failure AK2
• Due to accumulation of toxic metabolites ADA
• Due to abnormal actin polymerization CORO1A
Impaired cytokine-mediated signaling
• Due to defects of the common γ chain IG2RG (X-linked SCID)
• Due to defects of the IL-7R α chain IL7R
• Due to defects of Jak3 JAK3
Impaired signaling through the pre–T cell receptor
• Due to defective V(D)J recombination RAG1, RAG2, DCLRE1C, LIG4,* PRKDC
• Due to impaired expression of CD3 subunits CD3D, CD3E, CD3Z
Impaired signaling in the periphery ORA1
Unknown mechanism RMRP*

* These gene defects are most often associated with a milder clinical phenotype than SCID.

From Pessach I, Walter J, Notarangelo LD: Recent advances in primary immunodeficiencies: identification of novel genetic defects and unanticipated phenotypes, Pediatr Res 65:3R–12R, 2009.

Clinical Manifestations

Affected infants present within the 1st few months of life with recurrent or persistent diarrhea, pneumonia, otitis media, sepsis, and cutaneous infections. Growth may appear normal initially, but extreme wasting usually ensues after diarrhea and infections begin. Persistent infections with opportunistic organisms including Candida albicans, Pneumocystis jiroveci, parainfluenza 3 virus, adenovirus, respiratory syncytial virus, rotavirus vaccine virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus, measles virus, MMR-V vaccine virus, or bacillus Calmette-Guérin (BCG) lead to death. Affected infants also lack the ability to reject foreign tissue and are therefore at risk for severe or fatal graft versus host disease (GVHD) from T lymphocytes in nonirradiated blood products or in allogeneic stem cell transplants or less severe GVHD from maternal immunocompetent T cells that crossed the placenta while the infant was in utero.

Because all molecular types of SCID lack T cells, infants with SCID have lymphopenia (<2,500/mm3) that is present at birth, indicating that the condition could be diagnosed in all affected infants if white blood cell counts with manual differential counts were routinely performed on all cord bloods and the absolute lymphocyte count calculated. These infants also have an absence of lymphocyte proliferative responses to mitogens, antigens, and allogeneic cells in vitro. Patients with adenosine deaminase (ADA) deficiency have the lowest absolute lymphocyte counts, usually <500/mm3. Serum immunoglobulin concentrations are low or absent, and no antibodies are formed after immunizations. Analyses of lymphocyte populations and subpopulations demonstrate distinctive phenotypes for the various genetic forms of SCID (see Table 120-2). T cells are extremely low or absent in all types; when detected, in most cases they are transplacentally derived maternal T cells.

Treatment

SCID is a true pediatric emergency. Unless immunologic reconstitution is achieved through stem cell transplantation, death usually occurs during the 1st yr of life and almost invariably before 2 yr of age. If diagnosed at birth or within the 1st 3.5 mo of life, >94% of cases can be treated successfully with HLA-identical or T-cell–depleted haploidentical (half-matched) parental hematopoietic stem cell transplantation without the need for pretransplant chemoablation or post-transplant GVHD prophylaxis. ADA-deficient SCID and X-linked SCID have been treated with somatic gene therapy; although serious adverse events occurred in the case of X-SCID. These successes offer hope for gene therapy eventually becoming the treatment of choice for all forms of SCID for which the gene has been identified. ADA-deficient SCID is also managed with repeated injections of polyethylene glycol modified bovine adenosine deaminase (PEG-ADA).

X-Linked Severe Combined Immunodeficiency (SCIDX1) Due To Mutations in the Gene Encoding the Common Cytokine Receptor γ Chain (γC)

X-linked SCID (X-SCD) is the most common form of SCID in the USA, accounting for 47% of cases (Fig. 120-1). Clinically, immunologically, and histopathologically, affected individuals appear similar to those with other forms of SCID except for having uniformly low percentages of T and NK cells and an elevated percentage of B cells (T−, B+, NK−), a characteristic feature shared only with Janus kinase 3 (Jak3)–deficient SCID. The abnormal gene in X-SCD was mapped to Xq13, cloned, and found to encode the common γ chain (γc) for several cytokine receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The shared γc functions both to increase the affinity of the receptor for the respective cytokine and to enable the receptors to mediate intracellular signaling. Incapacitation of the receptors for all of these developmentally crucial cytokines by genetic mutations in γc provides an explanation for the severity of the immunodeficiency in SCIDX1. In the 1st 136 patients studied, 95 distinct mutations spanning all 8 IL2RG exons were identified, most of them consisting of small changes at the level of 1 to a few nucleotides. These mutations resulted in abnormal γc chains in two thirds of the cases and absent γc protein in the remainder. Carriers can be detected by demonstrating nonrandom X-chromosome inactivation or the deleterious mutation in their T, B, or NK lymphocytes. Unless donor B or NK cells develop, patients with X-SCID lack B- and NK-cell function after bone marrow transplantation because the abnormal γc persists in those host cells, despite excellent reconstitution of T-cell function by donor-derived T cells.

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Figure 120-1 Relative frequencies of the different genetic types among 203 patients with severe combined immunodeficiency seen consecutively over 4 decades. RAG, recombinase activating gene; Jak3, Janus kinase 3; ADA, adenosine deaminase; IL-7Rα, interleukin 7 receptor α chain.

Autosomal Recessive Severe Combined Immunodeficiency

This pattern of inheritance of SCID is less common in the USA than in Europe. Mutated genes on autosomal chromosomes have been identified in 12 forms of SCID: ADA deficiency; Jak3 deficiency; IL-7 receptor α chain (IL-7Rα) deficiency; RAG1 or RAG2 deficiency; Artemis deficiency; ligase 4 deficiency; DNA–protein kinase catalytic subunit (DNA-PKcs) deficiency; CD3δ, CD3ε, CD3ζ deficiency; and CD45 deficiency (see Fig. 120-1).

ADA Deficiency

An absence of the enzyme adenosine deaminase (ADA) is observed in approximately 15% of patients, the second most common form of SCID, resulting from various point and deletional mutations in the ADA gene on chromosome 20q13-ter. Marked accumulations of adenosine, 2′-deoxyadenosine, and 2′-O-methyladenosine lead directly or indirectly to T-cell apoptosis, which causes the immunodeficiency. ADA-deficient patients usually have a much more profound lymphopenia than do infants with other types of SCID, with mean absolute lymphocyte counts of <500/mm3; the absolute numbers of T, B, and NK cells are very low. NK function is normal. After T-cell function is conferred by hematopoietic stem cell transplantation without pretransplant chemotherapy, there is generally excellent B-cell function despite the fact that the B cells are of host origin. This is because ADA deficiency affects primarily T-cell function. Milder forms of ADA deficiency have led to delayed diagnosis of immunodeficiency, even to adulthood. Other distinguishing features of ADA-deficient SCID include the presence of rib cage abnormalities similar to a rachitic rosary and numerous skeletal abnormalities of chondro-osseous dysplasia, which occur predominantly at the costochondral junctions, at the apophyses of the iliac bones, and in the vertebral bodies where a “bone-in-bone” effect is observed.

As with other types of SCID, ADA deficiency can be cured by HLA-identical or haploidentical T-cell–depleted stem cell transplantation without the need for pre- or post-transplant chemotherapy; this remains the treatment of choice. Enzyme replacement therapy should not be initiated if stem cell transplantation is possible because it confers graft-rejection capability. Enzyme replacement provides protective immunity but over time there is a decline of lymphocyte counts and mitogenic proliferative responses. Fifteen infants with ADA deficiency have become immune reconstituted by gene therapy; in all cases, PEG-ADA was withheld. Spontaneous reversion to normal of a mutation in the ADA gene has also been reported.

Jak3 Deficiency

Patients with this autosomal recessive defect resemble all other types of SCID patients clinically. They have a lymphocyte phenotype similar only to that of patients with X-SCID, with an elevated percentage of B cells and very low or no T and NK cells. Because Jak3 is the only signaling molecule known to be associated with γc, it was a candidate gene for mutations leading to autosomal recessive SCID. Jak3 deficiency accounts for 6% of SCID cases. Even after successful T-cell reconstitution by transplantation of haploidentical stem cells, patients with Jak3-deficient SCID fail to develop NK cells or normal B-cell function owing to the defective function of those host cells that bear abnormal cytokine receptors that share γc.

IL-7Rα Deficiency

Patients with IL-7Rα-deficient SCID have a distinctive lymphocyte phenotype in that, though lacking T cells, they have normal or elevated numbers of both B and NK cells (T−, B+, NK+). This is the third most common form of SCID, accounting for 12% of cases in the USA (see Fig. 120-1). In contrast to patients with γc– and Jak3-deficient SCID, the immunologic defect in these patients is completely correctable by bone marrow stem cell transplantation, as the host B and NK cells appear to be normal.

RAG1 or RAG2 Deficiencies

Infants with these causes of SCID have a different lymphocyte phenotype from those of patients with SCID due to γc, Jak3, IL-7Rα, or ADA deficiencies in that they lack both B and T lymphocytes and have primarily NK cells in their circulation (T−, B−, NK+). This suggested a problem with their antigen receptor genes, which led to the discovery of mutations in recombinase-activating genes, RAG1 or RAG2. Such mutations result in a functional inability to form antigen receptors through genetic recombination. Omenn syndrome is an autosomal recessive, fatal condition characterized by profound susceptibility to infection with clonal T-cell infiltration of skin, intestines, liver, and spleen leading to an exfoliative erythroderma, lymphadenopathy, hepatosplenomegaly, and intractable diarrhea. Mutations in the recombinase activating genes, RAG1 and RAG2, have also been found in patients with this condition. These infants have persistent leukocytosis with marked eosinophilia and lymphocytosis; elevated serum IgE; low IgG, IgA, and IgM; and low or absent B cells. There is dominance of clonal TH2-like cells with severely impaired T-cell function due to the restricted heterogeneity of the host T-cell repertoire.

Artemis Deficiency

Another cause of SCID is a deficiency of a novel V(D)J recombination/DNA repair factor that belongs to the metallo-β-lactamase superfamily, which is encoded on chromosome 10p by a gene called Artemis. Deficiency of this factor results in an inability to repair DNA after double-stranded cuts by the RAG1 or RAG2 gene products in rearranging antigen receptor genes from their germ line configuration. Similar to RAG1- and RAG2-deficient SCID, this defect results in failure to develop T and B cells and is, therefore, another form of T−, B−, NK+ SCID, also called Athabascan SCID. There is increased radiation sensitivity of both skin fibroblasts and bone marrow cells of those affected with this type of SCID as well as with DNA-PKcs deficiency.

CD45 Deficiency

Other molecular defects causing SCID are mutations in the gene encoding the common leukocyte surface protein CD45. This hematopoietic cell–specific transmembrane protein tyrosine phosphatase functions to regulate src kinases required for T- and B-cell antigen receptor signal transduction. A 2 mo old male infant presented with a clinical picture of SCID and was found to have a very low number of T cells but a normal number of B cells. The T cells failed to respond to mitogens, and serum immunoglobulins diminished with time. He was found to have a large deletion on 1 CD45 allele and a point mutation causing an alteration of the intervening sequence 13 donor splice site on the other allele. A 2nd case of SCID due to CD45 deficiency has been reported, and the author has evaluated and treated a 3rd case.

CD3δ, CD3ε, and CD3ζ Deficiencies

Other causes of autosomal recessive SCID are deficiencies of components of the T-cell receptor (CD3δ, CD3ε, and CD3ζ chains). Mutations in the portions of these genes that encode the extracellular components of the proteins result in a profound deficiency of circulating mature CD3 T cells. Thus, CD3δ, CD3ε, and CD3ζ appear to be essential for intrathymic development of T cells. Since only T-cell development is affected in these defects, both B and NK cells are normal. Thus, the lymphocyte phenotype resembles that of SCID infants with IL-7Rα chain deficiency (T−B+NK+).

Reticular Dysgenesis

Reticular dysgenesis was 1st described in identical twin boys who exhibited a total lack of both lymphocytes and granulocytes in their peripheral blood and bone marrow. Of 8 infants with this defect, 7 died between 3 and 119 days of age as a result of overwhelming infections; 7 infants have been cured by bone marrow transplantation. The thymus glands have all weighed <1 g, have no Hassall corpuscles, and have few or no thymocytes. Reticular dysgenesis is considered a variant of SCID. The molecular basis of this autosomal recessive disorder has recently been found to be due to mutations in the gene encoding adenylate kinase 2.

120.2 Combined Immunodeficiency (CID)

Rebecca H. Buckley

CID is distinguished from SCID by the presence of low but not absent T-cell function. Similar to SCID, CID is a syndrome of diverse genetic causes. Patients with CID have recurrent or chronic pulmonary infections, failure to thrive, oral or cutaneous candidiasis, chronic diarrhea, recurrent skin infections, gram-negative bacterial sepsis, urinary tract infections, and severe varicella in infancy. Although they usually survive longer than infants with SCID, they fail to thrive and die early in life. Neutropenia and eosinophilia are common. Serum immunoglobulins may be normal or elevated for all classes, but selective IgA deficiency, marked elevation of IgE, and elevated IgD levels occur in some cases. Although antibody-forming capacity is impaired in most patients, it is not absent.

Studies of cellular immune function show lymphopenia, profound deficiencies of T cells, and extremely low but not absent lymphocyte proliferative responses to mitogens, antigens, and allogeneic cells in vitro. Peripheral lymphoid tissues demonstrate paracortical lymphocyte depletion. The thymus is very small with a paucity of thymocytes and usually no Hassall corpuscles. An autosomal recessive pattern of inheritance is common.

Purine Nucleoside Phosphorylase Deficiency

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