Primary Immunodeficiency Syndromes Research Articles

Human Immunodeficiency Syndromes Affecting Human Natural Killer Cell Cytolytic Activity

Natural killer (NK) cells are lymphocytes of the innate immune system that secrete cytokines upon activation and mediate the killing of tumor cells and virus-infected cells, especially those that escape the adaptive T cell response caused by the down regulation of MHC-I. The induction of cytotoxicity requires that NK cells contact target cells through adhesion receptors, and initiate activation signaling leading to increased adhesion and accumulation of F-actin at the NK cell cytotoxic synapse. Concurrently, lytic granules undergo minus-end directed movement and accumulate at the microtubule-organizing center through the interaction with microtubule motor proteins, followed by polarization of the lethal cargo toward the target cell. Ultimately, myosin-dependent movement of the lytic granules toward the NK cell plasma membrane through F-actin channels, along with soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent fusion, promotes the release of the lytic granule contents into the cleft between the NK cell and target cell resulting in target cell killing. Herein, we will discuss several disease-causing mutations in primary immunodeficiency syndromes and how they impact NK cell-mediated killing by disrupting distinct steps of this tightly regulated process.

Genetic defects and the role of helper T-cells in the pathogenesis of common variable immunodeficiency

Common variable immunodeficfiiency (CVID) is a primary immunodeficiency syndrome representing a heterogeneous set of disorders resulting mostly in antibody deficiency and recurrent infections. However, inflammatory and autoimmune disorders and some kinds of malignancies are frequently reported as a part of the syndrome. Although it is one of the most widespread primary immunodeficiency, only recently some genetic defects in CVID have been identified. Mutations have been detected in inducible T-cell costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell activating factor-receptor (BAFF-R), B-cell receptor complex (CD19, CD21 and CD81) and CD20. On the other hand, recent studies have shown a decrease in T-helper-17 cells frequency and their characteristic cytokines in CVID patients and this emphasis on the vital role of the T-cells in immunopathogenesis of the CVID. Furthermore, in the context of autoimmune diseases accompanying CVID, interleukin 9 has recently attracted a plenty of considerations. However, the list of defects is expanding as exact immunologic pathways and genetic disorders in CVID are not yet defined. In this review, we have a special focus on the immunopathogenesis of CVID, recent advances in understanding the underlying etiology and genetics for patients.

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Introduction: A 2-month-old male was transferred to the pediatric intensive care unit after 1 month hospitalization in several other institutions. He had failure to thrive, vomiting, diarrhea, hypoglycemia, metabolic acidosis, and elevated liver enzymes. He had tachypnea, which had been explained as a compensatory to the degree of metabolic acidosis. The working diagnosis was inborn error of metabolism, but initial testing failed to reveal the diagnosis and the metabolic team signed off. Upon review of his chest radiography, absence of a thymus shadow was noted, as was interstitial pneumonitis. Bronchoscopy was performed; bronchoalveolar lavage indicated pneumonia due to Pneumocystis jirovecii. Appropriate therapy was initiated. Further tests for immunodeficiency remained puzzling as no primary immunodeficiency syndrome could be identified. The metabolic team was involved again and testing for congenital disorder of glycosylation (CDG) was sent, given a few reports of associated immunodeficiency. Final result of chromosomal analysis showed two phosphomannomutase 2 (PMM2) gene mutations, consistent with CDG Ia. Despite initial improvement (11 days of extubation and enteral feeds), clinical deterioration occurred (pleural and pericardial effusions and acute respiratory failure). He had worsening renal function and oliguria; he also developed seizures. Ultimately, the family opted to withdraw care. PMM2-CDG, or CDG Ia, is the most common disorder of N-linked glycosylation defects. Patients with CDG Ia exhibit clinical variability: they may present as neonates with hydrops, pericardial effusion, ascites, and death; or they may present later in infancy with hypotonia, dysmorphic features, and developmental delay. Milder phenotypes have been described. A case series detailed the spectrum of CDG Ia phenotypes, further categorizing them into neurological and multivisceral subtypes. None of these patients exhibited lung involvement or immunodeficiency. Our patient presented with an opportunistic infection and immune dysfunction, likely secondary to his underlying CDG Ia. To the best of our knowledge, infection with Pneumocystis jirovecii pneumonia in this context has not previously been described.

Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs(∗)7), in NFKB2 affecting the C terminus of NF-κB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-affected individuals uncovered a second heterozygous nonsense mutation, c.2557C>T (p.Arg853(∗)), in one simplex case. Affected individuals in both families presented with an unusual combination of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and adrenal insufficiency. NF-κB2 is the principal protein involved in the noncanonical NF-κB pathway, is evolutionarily conserved, and functions in peripheral lymphoid organ development, B cell development, and antibody production. In addition, Nfkb2 mouse models demonstrate a CVID-like phenotype with hypogammaglobulinemia and poor humoral response to antigens. Immunoblot analysis and immunofluorescence microscopy of transformed B cells from affected individuals show that the NFKB2 mutations affect phosphorylation and proteasomal processing of p100 and, ultimately, p52 nuclear translocation. These findings describe germline mutations in NFKB2 and establish the noncanonical NF-κB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome.

Loss-of-Function Mutations in the IL-21 Receptor Gene Cause a Primary Immunodeficiency Syndrome

D Kotlarz, N Zietara, G Uzel. J Exp Med. 2013;210(3):433–443 This report of 2 unrelated kindreds with newly recognized mutations in the inteleukin-21 receptor gene (IL-21R) highlights the molecular basis and phenotype of a new form of immunodeficiency. Two sets of kindreds were studied. The first set included a 4-year-old boy and a 10-year-old sister born from consanguineous Lebanese parents with phenotypes characterized by recurrent respiratory infections and chronic cryptosporidial gastrointestinal infection and associated chronic cholangitis, biliary fibrosis, and cirrhosis. A second unrelated set included an 8-year-old boy and a 13-year-old …

SAP modulates B cell functions in a genetic background-dependent manner

Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP−/− CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP−/− animals. It is however not well understood whether in XLP patients and SAP−/− mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP−/− mice and in Rag−/− mice into which B cells derived from SAP−/− mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP−/− mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP−/− mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP−/− mice, suggests potentially novel therapeutic interventions in subsets of XLP patients.

Interleukin-21 Overexpression Dominates T Cell Response to Epstein-Barr Virus in a Fatal Case of X-Linked Lymphoproliferative Syndrome Type 1

Interleukin-21 (IL-21) is a cytokine whose actions are closely related to B cell differentiation into plasma cells as well as to CD8(+) cytolytic T cell effector and memory generation, influencing the T lymphocyte response to different viruses. X-linked lymphoproliferative syndrome type 1 (XLP-1) is a primary immunodeficiency syndrome that is characterized by a high susceptibility to Epstein-Barr virus. We observed in a pediatric patient with XLP-1 that IL-21 was expressed in nearly all peripheral blood CD4(+) and CD8(+) T cells. However, IL-21 could not be found in the lymph nodes, suggesting massive mobilization of activated cells toward the infection's target organs, where IL-21-producing cells were detected, resulting in large areas of tissue damage.

Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome

Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.

A Young Girl with Repeated Episodes of Pneumonia and Intermittednt Diarrhoea - The Primary Immunodeficiency Syndrome

A description is given of a case of a young girl who presented with repeated episodes of pneumonia since childhood. In addition, she had episodes of intermittent diarrhoea. Her investigative work-up revealed a deficiency of serum immunoglobulins. The profile was suggestive of common variable immunodeficiency. Because of a relative rarity of this disease, it is often misdiagnosed earlier. Late diagnosis and delayed institution of immunoglobulin replacement therapy results in increased morbidity with a wide variety of organ-specific complications and increased mortality. DOI: http://dx.doi.org/10.3329/bjmed.v22i1.13597 Bangladesh J Medicine 2011; 22: 24-26

Mismatched related hematopoietic stem cell transplantation in primary immunodeficiency

Hematopoietic stem cell transplantation (HSCT) is the definitive therapy for a variety of primary immunodeficiency syndromes (PIDs). However, no more than 30% of the patients will have a human leukocyte antigen (HLA)-identical sibling. We retrospectively analyzed our results of ten patients with PID; severe combined immunodeficiency (SCID) (n = 7), hyper IgM (HIgM) (n = 1) and combined immunodeficiency (CID) (n = 2), who lacked a fully matched donor and underwent mismatched related HSCT during the period from 2008 to 2010. The median age at the time of transplantation ranged between 3 and 84 months (median 6.5 months). Peripheral blood stem cells (PBSC) were used in all HSCTs. The mean value of the peripheral CD34+ cells infused was 9.19 × 10 (6) /kg recipient weight. Patients received different conditioning protocols. All patients received anti graft versus host disease (GVHD) prophylaxis and all were engrafted. Mixed chimerism (5-55%) was noticed. GVHD was observed in 50% of the patients. Post-transplant follow-up ranged from 3 weeks to 36 months (median 15 months). Five patients are still alive while one patient developed engraftment syndrome followed by graft slippage for which a second transplant with CD34+ stem cells 5.8 × 10 (6) /kg recipient's weight was infused. The others died from sepsis and transplant-related complications. Immune reconstitution was noticed in four patients. In conclusion, HLA-haploidentical stem cell transplantation may be feasible, with appropriate GVHD prophylaxis, for patients with PID who lack a fully matched donor.

Hemophagocyctic lymphohistiocytosis developed in a Japanese boy with Chédiak-Higashi syndrome

Chédiak-Higashi syndrome (CHS) is one of the primary immunodeficiency syndromes accompanied by oculocutaneous albinism. It is characterized by existence of giant granule of neutrophils, and development of symptoms of hemophagocytic lymphohistiocytosis. CHS is a rare disorder and recognition of the disease is indispensable for its diagnosis. In our case, a four-month-old boy, virus-associated hemophagocytic syndrome (VAHS) was suspected from generation of fever, hepatosplenomegaly, and existence of atypical lymphocytes on admission. However, elevation of serum AST, LDH and ferritin were quite slight as VAHS, and rapid exacerbation of the findings was not seen. Associated virus was undetected. He was finally diagnosed as CHS developing hemophagocyctic lymphohistiocytosis based on the existence of a giant granule of neutrophils in the peripheral blood smear and oculocutaneous albisum and laboratory findings. Clinical outcome was successful after receiving HLA-matched unrelated bone marrow transplantation.

Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disease-causing intronic loss-of-function mutation in SH2D1A. The intronic mutation affected SH2D1A gene transcription but not mRNA splicing, and led to markedly reduced level of SAP protein. Despite undetectable serum immunoglobulins, the patient's B cells replicated and differentiated into antibody producing cells normally in vitro.

Combating Cancer Predisposition in Association With Idiopathic Immune Deficiency: A Recurrent Nodal and Cutaneous T-Cell Lymphoproliferative Disease in a Patient With Cartilage-Hair Hypoplasia

Address for correspondence: Mervi Taskinen, MD, Department of Pediatrics, Children’s Hospital, Helsinki University Central Hospital, PO Box 281 and 00029 HUS, Helsinki, Finland Clinical Pra ● Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by severe short-limbed short stature and hypoplastic hair. CHH is a primary immunodeficiency syndrome with impairment of cellular immunity in more than 85% of the patients. In addition, CHH is a cancer syndrome, with a 7-fold increase in incidence of cancer. The most frequent cancer diagnoses have been non-Hodgkin lymphoma of B-cell origin and basal cell carcinoma. ● We report on a male patient with CHH who developed 2 clinically distinct and altering CD30 T-cell lym-

Lymphoma complicating primary immunodeficiency syndromes

One of the strongest arguments for the immune surveillance network of antibodies and sensitized cytotoxic T cells is the extraordinary incidence of lymphoid malignancy in the many types of primary immunodeficiency. This review updates the literature that seems to wax and wane on the importance of specific immunity to malignant cell antigens by previous authors. This new survey strongly supports the tenet that immune responses protect from malignant cell growth and development, much like it protects against a hostile microbial world. As more genetic lesions are discovered that cause various forms of immune deficiency, each with their consequent type of infection or malignancy, the notion that certain devastating infections or malignancies develop by chance is becoming less likely. The predominance of B-cell lymphoma in immune-deficient patients is both interesting and vexing. One might reasonably ask why the entire spectrum of malignancies is not seen in primary immunodeficiency. Regardless of continuing debate on immune surveillance of malignancy, the evidence presented in this review strongly supports that it has a key role in preventing lymphoid malignancy.

Streptococcus B septic polyarthritis revealing Good's syndrome

We report on a 46-year-old woman, who developed streptococcus B septic polyarthritis in the context of septicemia of urinary origin. This case revealed a Good's syndrome whose diagnosis was made on the basis of a profound hypogammaglobulinaemia, a large decrease of peripheral B cells and a thymoma disclosed on chest computed tomography (CT) and confirmed by surgical removal (AB type). There was also an inversion of the peripheral CD4+/CD8+ T cell ratio and an increase of CD8+ T cells. The course of infection was favorable under treatment with antibiotics and intravenous immunoglobulin. Good's syndrome is a rare entity, which belongs to primary immunodeficiency syndromes. Its first manifestations appear late in life, usually after the age of 40. In front of hypogammaglobulinemia, it is necessary to search for Good's syndrome by practicing chest CT scan, looking for thymoma, which is constant, and peripheral lymphocytes phenotyping looking for B cell lymphopenia and the frequent T cell associated abnormalities.

CNS Complications in Immunodeficiency Syndromes Due to Mutations in Transcription Factors STAT-1 and GATA-2 (S57.003)

Objective: To describe CNS complications of immunodeficiency syndromes. Background CNS complications of patients with congenital immunodeficiencies are poorly understood. STAT1 and GATA2 are transcription factors that regulate interferon-mediated immune responses and early hematopoiesis, respectively. STAT1 mutations predispose to infection with nontuberculous mycobacteria (NTM), viruses, or mucocutaneous candida, depending on the location of the effect of the mutation. Deficiencies in GATA2 are associated with recurrent infection with NTM, monocytopenia, and transformation to myelodysplastic syndrome/acute myelogenous leukemia. Design/Methods: Three patients from the Neurology Consult Service at the NIH are described with regards to their immunodeficiency syndromes and their neurological presentations. Results: A 22 year old woman with a STAT1 mutation presented with brain lesions and an intramedullary spinal cord lesion due to disseminated coccidioidomycosis, which was refractory to antifungal therapy. Typically, coccidioidomycosis in the CNS infects the intradural and extramedullary spaces. A 3 year old boy with a STAT1 mutation presented with multiple intracranial aneurysms and subarachnoid hemorrhage. While STAT1 protein defects are associated with abdominal aneurysms in the setting of chronic inflammation, CNS aneurysms are recently recognized with gain of function STAT1 mutations. A 38 year old woman with a GATA2 mutation and myelodysplasia developed three deep vein thromboses in five years, followed by multiple cardioembolic strokes due to culture negative subacute endocarditis. The mechanism for her hypercoagulability, and that of other patients with GATA2monomac deficiency is unknown, but GATA2 regulates endothelial gene expression, as well. Conclusions: Neurological signs and symptoms in patients with recurrent infection should prompt the neurologist to consider primary immunodeficiency syndromes. STAT1 and GATA2 transcription factors may predispose patients to vascular as well as infectious CNS complications. The overlap between chronic infection and inflammatory complications, such as cord edema or an inflammatory-type vasculopathy, presents additional challenges in management, since direct immunosuppression is usually not possible. Disclosure: Dr. Kranick has nothing to disclose. Dr. Holland has nothing to disclose. Dr. Uzel has nothing to disclose. Dr. Nath has nothing to disclose.

The Clinical Characterstics of Aseptic Meningitis with Selective IgG Subclass 3 Deficiency (S57.004)

Objective: To examine serum IgG subclass analysis among aseptic meningitis patients, and to clarify characteristics of aseptic meningitis with selective IgG subclass 3 deficiency. Background Selective IgG subclass 3 deficiency is one of the primary immunodeficiency syndromes. This defect is known to be associated with recurrence or prolongation of the mainly viral upper or lower respiratory infection in children and adults. Previously only 3 cases of recurrent aseptic meningitis with selective IgG subclass 3 deficiency have been reported in adult. We hypothesized that aseptic meningitis with selective IgG subclass 3 deficiency is present in the chronic or recurrent meningitis. Design/Methods: The study included aseptic meningitis patients (age≥16 years; 18 patients (acute 11 patients; chronic 7 patients). All patients were not associated with collagen diseases, or meningeal carcinomatosis. We analyzed the serum concentration of IgG subclass 1, 2, 3, 4 in these patients in acute phase. We detected 8 patients with selective IgG subclass 3 deficiency (below 20 mg/dL), and 10 patients with normal concentration of IgG subclass 3 and other subclasses. We compared the clinical symptoms, clinical course, parameters of cerebrospinal fluid (cell counts, total protein, glucose) in acute phase between patients with selective IgG subclass 3 deficiency and those with normal IgG subclass 3. Data were statistically assessed by the chai-square test or t-test. Results: The patients with selective IgG subclass 3 deficiency presented highly chronic course (p Conclusions: The clinical characteristics of aseptic meningitis with selective IgG subclass 3 deficiency are chronic or recurrent meningitis. Disclosure: Dr. Hayashi has nothing to disclose. Dr. Yamada has nothing to disclose. Dr. Yoshikura has nothing to disclose. Dr. Harada has nothing to disclose. Dr. Koumura has nothing to disclose. Dr. Sakurai has nothing to disclose. Dr. Kimura has nothing to disclose. Dr. Inuzuka has nothing to disclose.

The phenotype of human STK4 deficiency

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.

Adaptive Immune Response to Model Antigens Is Impaired in Murine Leukocyte-Adhesion Deficiency-1 Revealing Elevated Activation ThresholdsIn Vivo

Absence of β 2 integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary immunodeficiency syndrome. Although extensive in vitro work has established an essential function of β 2 integrins in adhesive and signaling properties for cells of the innate and adaptive immune system, their respective participation in an altered adaptive immunity in LAD1 patients are complex and only partly understood in vivo. Therefore, we investigated adaptive immune responses towards different T-dependent antigens in a murine LAD1 model of β 2 integrin-deficiency (CD18−/−). CD18−/− mice generated only weak IgG responses after immunization with tetanus toxoid (TT). In contrast, robust hapten- and protein-specific immune responses were observed after immunization with highly haptenated antigens such as (4-hydroxy-3-nitrophenyl)21 acetyl chicken γ globulin (NP21-CG), even though regularly structured germinal centers with specificity for the defined antigens/haptens in CD18−/− mice remained absent. However, a decrease in the hapten/protein ratio lowered the efficacy of immune responses in CD18−/− mice, whereas a mere reduction of the antigen dose was less crucial. Importantly, haptenation of TT with NP (NP-TT) efficiently restored a robust IgG response also to TT. Our findings may stimulate further studies on a modification of vaccination strategies using highly haptenated antigens in individuals suffering from LAD1.