Selective IgA Deficiency in Children in Israel

IgA deficiency is the most common human primary immune-deficiency. We evaluated the clinical and immunological characteristics of selective IgA deficiency in children in Israel. The study group included 63 children diagnosed with IgA deficiency from 1987 to 2005. Mean follow-up time per child was 10.6 years. Average age at diagnosis was 10.5 years. In one child, the IgA deficiency was transient. Infectious diseases, mainly recurrent pneumonia and ear infection, were common and occurred in 25 patients (39.7%). Allergic diseases were documented in 20 (31.7%) of our patients. Thirteen children (20.6%) had autoimmune diseases. Malignancies were diagnosed in three children (4.8%), an association that has not been reported in previous series. IgA deficiency appears to be a risk factor for infections, allergic diseases, autoimmune conditions, and malignancy.     

Nephrotic syndrome in a patient with IgA deficiency-associated mesangioproliferative glomerulonephritis

A case of mesangioproliferative glomerulonephritis in a 55-year-old woman with selective IgA deficiency and serum antinuclear antibodies who presented with nephrotic syndrome is described. The patient did not have clinical or laboratory features of systemic lupus erythematosus (SLE) other than antinuclear antibodies. Histology of the patient's renal biopsy revealed a mesangioproliferative glomerulonephritis and direct immunofluorescence showed that paramesangial deposits contained predominant IgM with lesser IgG, C3 and C1q. These findings are identical to those previously described in a form of glomerulonephritis associated with IgA deficiency and would be atypical for lupus nephritis. Glomerulonephritis is not a well recognized complication of IgA deficiency, though it has been rarely reported in the literature. This case provides further evidence that IgA deficiency is associated with a unique immune complex-mediated glomerulopathy with characteristic immunopathological and ultrastructural features. It is the first reported case to present with nephrotic syndrome.     

Panhypogammaglobulinemia in systemic lupus erythematosus: in vitro demonstration of multiple cellular defects

Classically, systemic lupus erythematosus (SLE) is a disease of antibody overproduction, whereas the hallmark of acquired immune deficiency is antibody underproduction. Two patients are presented in whom panhypogammaglobulinemia developed during the course of SLE. In both patients, the levels of the major immunoglobulin (Ig) classes did not fall simultaneously. Anti-DNA antibodies were present, and exacerbations of SLE nephritis occurred in both cases 6 to 8 yr after Ig levels became subnormal. One patient still requires immunosuppressive therapy for renal disease; both patients are experiencing recurrent sinopulmonary bacterial infections. In the pokeweed mitogen-stimulated Ig biosynthesis assay, both patients showed abnormal Ig production due to defective function of three cell types: hyporesponsive B cells, excessive T suppression, and subnormal T help. The latter defect is rare in common variable hypogammaglobulinemia. One patient also showed extreme suppression of Ig production by phagocytic mononuclear cells. Thus, despite the similarity in the histories, the cellular function of these two patients was not identical in vitro.     

Index to volume 69

Classically, systemic lupus erythematosus (SLE) is a disease of antibody overproduction, whereas the hallmark of acquired immune deficiency is antibody underproduction. Two patients are presented in whom panhypogammaglobulinemia developed during the course of SLE. In both patients, the levels of the major immunoglobulin (Ig) classes did not fall simultaneously. Anti-DNA antibodies were present, and exacerbations of SLE nephritis occurred in both cases 6 to 8 yr after Ig levels became subnormal. One patient still requires immunosuppressive therapy for renal disease; both patients are experiencing recurrent sinopulmonary bacterial infections. In the pokeweed mitogen-stimulated Ig biosynthesis assay, both patients showed abnormal Ig production due to defective function of three cell types: hyporesponsive B cells, excessive T suppression, and subnormal T help. The latter defect is rare in common variable hypogammaglobulinemia. One patient also showed extreme suppression of Ig production by phagocytic mononuclear cells. Thus, despite the similarity in the histories, the cellular function of these two patients was not identical in vitro.     

Phenotypic characteristics of three human non-Hodgkin lymphoma lines: flow cytometric analysis after long-term maintenance.

Recently, we reported on the importance of food antigens on the pathogenesis of an experimentally-induced model of, and some patients with, IgA nephropathy. In this paper, the glomerular deposition of food antigens (casein, lactalbumin, peanut protein, soy bean protein, rice protein, ovalbumin) was investigated by an immunofluorescence technique in 28 patients with IgA nephropathy and 32 controls (ten with lupus nephritis, three with Henoch-Schoenlein purpura nephritis and 19 with other glomerulonephritis). Glomerular IgA deposition was demonstrated in all IgA nephropathy and Henoch-Schoenlein purpura nephritis, and in four lupus nephritis. Positive findings of food antigens, observed as mesangial pattern, were obtained in eleven cases (39.3%) with casein, 21 (75.0%) with soy bean protein and one (3.6%) with rice protein in IgA nephropathy, even though no such findings were seen in the control group. Eleven of 28 patients with IgA nephropathy were positive with soy bean protein alone, nine were positive with soy bean protein + casein, one was positive with soy bean protein + casein + rice protein, and one was positive with casein alone. The deposition of food antigens was not observed in six cases only. Furthermore, no correlation was noted between the deposition of food antigens and the deposition of IgA1, IgA2 or J chain, in vitro binding of the secretory component, or histopathological grades. These results suggest that the exact meanings of glomerular deposition are unclear. Food antigens are postulated, however, as possibly participating strongly in the pathogenesis and as being localized in the glomerular mesangium as an antigen in some patients with IgA nephropathy.     

Immunological and clinical features of pediatric patients with primary hypogammaglobulinemia in Taiwan

We retrospectively reviewed the clinical and immunological features as well as the outcome of children with a diagnosis of primary hypogammaglobulinemia, who were treated at the National Taiwan University Hospital between 1984 and 2001. A total of 33 patients were enrolled: seventeen patients with common variable immunodeficiency (CVID), six patients with selective immunoglobulin deficiencies (one subclass IgA and five IgG), four patients with severe combined immunodeficiency (SCID), three patients with transient hypogammaglobulinemia of infancy (THI) and three patients with X-linked (Bruton) agammaglobulinemia (XLA). In addition to recurrent sinopulmonary infections and prolonged fever, allergic diseases are noted in 76% of CVID patients and 100% of patients with selective immunodeficiencies. Immunoglobulin levels were extremely low in XLA and decreased in CVID patients. Three SCID patients had decreased mean absolute lymphocyte counts of 290/mm3. Long-term complications included bronchiectasis in 2 XLA patients, 2 CVID patients and 1 patient with selective immunodeficiency; short stature in one of each XLA, SCID, and CVID patients respectively; poor school performance in 2 SCID patients and 1 XLA patient; and hemolytic anemia in 1 CVID patient. We concluded that in addition to a thorough physical examination, a family history of early death from infection and past history of neonatal hyperbilirubinemia, are crucial in evaluating a patient with suspicious primary hypogammaglobulinemia. The associated symptoms of primary hypogammaglobulinemia, such as recurrent sinopulmonary infections, prolonged fever and allergic diseases, are also diagnostic clues. In the treatment of hypogammaglobulinemia, early and regular high doses of Intravenous immunoglobulin (IVIG) supplement may avoid the development or decrease the severity of bronchiectasis.     

Quantitative immunoglobulins and IgG subclasses in patients with corticosteroid-dependent reversible airway obstruction

Six of 12 patients with corticosteroid-dependent bronchial asthma and recurrent sinopulmonary infections were found to have significant abnormalities in quantitative immunoglobulins and/or IgG subclasses. Five patients had a combined quantitative immunoglobulin and IgG subclass deficiency and one patient had an isolated IgG deficiency. Combined IgG subclass deficiencies were observed in two patients, both with deficiencies of IgG2 and IgG3. The most common IgG subclass deficiencies were of IgG2 and IgG3, which were found in three patients each.     

Renal biopsies in Johor: a 7-year study

Consecutive renal biopsies received from 1994 to 2000 in Johor Bahru were reviewed. There were 441 cases, of which 407 were adequate biopsies (92.3%). Lupus nephritis formed the largest diagnostic entity (126 cases, 31.0%). This reflected the high prevalence of systemic lupus erythematosus (SLE) patients in Malaysia. The most common histological pattern of lupus nephritis was diffuse proliferative glomerulonephritis: WHO Class IV (96 cases, 76.2%). Other diagnostic entities were minimal change disease (28.5%), proliferative glomerulonephritis (10.6%), IgA nephropathy (9.8%), focal glomerulosclerosis (4.9%), membranous glomerulonephritis (4.4%), transplant rejection (3.9%), end stage nephropathy (3.4%) and others (3.4%). The morphological pattern of renal biopsies in Johor was similar to that reported in the University Hospital Kuala Lumpur.     

Autoantibodies in patients with IgA and IgG2 deficiencies

Patients with primary immunodeficiencies have a high incidence of autoantibodies, mainly of no clinical significance. It has recently been suggested that patients with a combined IgA-IgG2 deficiency have more autoantibodies than those patients with isolated deficiencies. We have studied 42 patients with selective IgA deficiency, nine with isolated IgG2 deficiency and 13 with combined IgA-IgG2 deficiency, and have found that the combined IgA-IgG2 deficiency has no influence on autoantibody prevalence, except for anti-IgA antibodies. The presence of chronic respiratory infections (a clinical feature commonly associated with both selective IgA and IgG2 deficiencies) is unrelated to the prevalence of autoantibodies. The most frequent autoantibodies found are anti-IgA and anti-cardiolipin. Most of the autoantibodies have been found to be devoid of actual clinical significance. Only three patients had overt autoimmune disease.     

IgG Subclasses and Antibody Response to Pneumococcal Capsular Polysaccharides in Children with Severe Sinopulmonary Infections and Asthma

A prospective open study was carried out on 30 pediatric patients with most severe chest disease whose serum immunoglobulin levels were normal. The patients entered into the study had had two or more documented episodes of pneumonia, and/or six episodes of bronchitis with fever within a year, and/or severe asthma (steroid-dependent), and/or hospitalization for chest disease for more than 30 days within the year preceding the study. Eleven patients had sinopulmonary infections, 19 had asthma. Twenty patients had low levels of one or two IgG subclasses: 11 were deficient in IgG3, three in IgG4, three in IgG3 + IgG4, and three in IgG2 + IgG4. Patients with low IgG subclass levels were distributed throughout the different clinical entities. These children had significantly longer periods of hospitalization than the patients in whom all IgG subclasses were within the normal range. They suffered more often from sinopulmonary infections. Asthmatic children with low levels of an IgG subclass reported more days with wheezing and needed more steroids than the children without subclass deficiencies.     

Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency

We studied 20 children with recurrent sinopulmonary infections and serum IgG levels within the normal range, who had selective IgG-subclass deficiency. Twelve of the children were IgG2 deficient, five were IgG3 deficient, and three were deficient in both IgG2 and IgG3. IgA deficiency was present in 3 of the 20 patients. In the children with IgG2 deficiency, serum antibody concentrations to the capsular polysaccharide of Hemophilus influenzae type B (Hib) were significantly lower than those in age-matched controls, both before and after immunization with the Hib capsular polysaccharide antigen, which elicits antibody predominantly of the IgG2 subclass. In contrast, their serum antibody titers to the tetanus and diphtheria toxoid protein antigens, which elicit antibody predominantly of the IgG1 subclass, were normal in comparison with those of age-matched controls. These results suggest that impairment of the antibody response to specific microbial antigens predisposes patients with selective IgG-subclass deficiencies to recurrent infections. Thus, as an aid in determining therapy, children with recurrent infections and normal total serum IgG should be evaluated for this condition.     

Progression of selective IgA deficiency to common variable immunodeficiency

Selective IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Although it is often asymptomatic, selected patients show an increased frequency of infections, allergies and autoimmune manifestations. Common variable immunodeficiency (CVID) is a primary antibody deficiency disease that shares many clinical features with IgAD. A common genetic basis for IgAD and CVID has been suggested based on their occurrence in members of the same family and the similarity of the underlying B cell defects. Progression from IgAD to CVID has also been reported in several cases. Here we present 4 patients with IgAD and autoimmune features who subsequently developed CVID. All symptomatic IgAD patients, especially those with associated IgG subclass deficiency or autoimmune features, should be monitored for evolution to CVID. Early diagnosis of this conversion and institution of immunoglobulin therapy is effective in preventing severe bacterial infections and pulmonary insufficiency.     

Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital.

BACKGROUND: Advances in immunologic techniques in recent years have led to increased recognition of primary immunodeficiency disorders, with IgA deficiency the most common phenotype reported by most registries. There have also been reports of increased associated incidence of autoimmunity, allergy, and other diseases. OBJECTIVES: We wished to determine the percentage of different primary immunodeficiency disorders seen in a pediatric tertiary hospital and to determine the association of primary immunodeficiency disorders with other diseases that are not part of classic immunodeficiency disorders. METHODS: We performed a retrospective review of the patients referred to our allergy/immunology clinic for immunologic evaluation of recurrent infections during an 8-year period. We also reviewed pathology reports with postmortem diagnosis of immunodeficiencies not identified while patients were alive. RESULTS: Of the 91 patients with primary immunodeficiency disorders evaluated, the majority had predominantly antibody deficiencies (67%). The most common phenotype was specific antibody deficiency with normal immunoglobulins (23.1%), defined as inability to mount an adequate response to pneumococcal polysaccharides followed by IgG2 subclass deficiency (17.6%). These two phenotypes were diagnosed mostly in the last 2 years of the survey. Associated diseases, found in 40% of patients, were mostly allergic conditions followed by syndromic/chromosomal disorders. CONCLUSION: The study reveals that specific antibody deficiency with normal immunoglobulins followed by IgG2 subclass deficiency was the most frequently diagnosed primary immunodeficiency disorder in our patient population. It also indicates that immunodeficiency disorders should be considered in patients with other abnormalities like allergic and syndromic/chromosomal disorders that present with recurrent infections.     

Solubilization of intraglomerular deposits of IgG immune complexes by human sera or gamma-globulin in patients with lupus nephritis.

A study of the solubilization of glomerular deposition of IgG immune complexes by sera from patients with lupus nephritis is described. Renal biopsy specimens were obtained from 11 patients with lupus nephritis, five patients with IgA nephropathy and one patient with minimal change nephrotic syndrome. These renal specimens were incubated with fresh, stored or heated sera from the same patients or healthy adults and human gamma-globulins at 37 degrees C for 1 h in plastic test tubes. The sections were stained with FITC conjugated heavy chain specific anti-human IgG or C3 antisera and then examined with a fluorescent microscope. The sections were also stained with FITC conjugated human gamma-globulins and rhodamine conjugated anti-human IgG, IgM or IgA antisera and then examined by double exposure under a fluorescent microscope. It was demonstrated that fresh human sera or gamma-globulins significantly solubilize glomerular immune deposits in patients with lupus nephritis in vitro. It was indicated that the solubilization of IgG glomerular deposits from patients with lupus nephritis does not depend on complement. It is postulated that solubilization of immune deposits in glomeruli requires the excess amounts of antigenic substances in patients with lupus nephritis.     

Selective IgA Deficiency

Introduction  

Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency defined as decreased serum level of IgA in the presence of normal levels of other immunoglobulin isotypes. Most individuals with IgA deficiency are asymptomatic and identified coincidentally. However, some patients may present with recurrent infections of the respiratory and gastrointestinal tracts, allergic disorders, and autoimmune manifestations.     

Cytomegalovirus antigenemia assay as a useful tool for early diagnosis and therapy for cytomegalovirus infections in three cases with collagen diseases]

We report here three cases of collagen diseases with cytomegalovirus infections. (1) A 21-year-old female, who had been diagnosed as systemic lupus erythematosus, lupus nephritis and lupus peritonitis, had fever. Cytomegalovirus antigenemia (CMV-Ag) assay was 10/8 positive. (2) A 33-year-old female, who had been diagnosed as Wegener glanulomatosis, had fever and liver dysfunction. CMV-Ag assay was 933/896 positive. (3) A 64-year-old female, who had been diagnosed as microscopic polyangitis, had fever, liver dysfunction and pneumonia. CMV-Ag assay was 6/2 positive. They were considered to be complicated with CMV infections. We could make early diagnoses of CMV infection by using CMV-Ag assay and treat them with anti-CMV therapy effectively.     

Anti-C1q autoantibodies specific against the globular domain of the C1qB-chain from patient with lupus nephritis inhibit C1q binding to IgG and CRP

Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus. Higher titers of serum anti-C1q autoantibodies correlate with disease activity in patients with lupus nephritis. Anti-C1q autoantibodies have been shown to bind neo-epitopes within the collagen region of human C1q. In a preliminary study, we recently reported that the anti-C1q autoantibodies could also recognize epitopes within the globular domain (gC1q) of the C1q molecule. Here, 38 sera from patients with renal biopsy-proven lupus nephritis were screened for the presence of anti-gC1q autoantibodies, using recombinant globular head regions of individual A (ghA), B (ghB) and C (ghC) chains of human C1q. We isolated anti-gC1q autoantibodies from three selected patients. Human C1q was pre-incubated with increasing concentrations of the isolated anti-ghA, anti-ghB or anti-ghC autoantibodies and its binding to different C1q target molecules such as IgG and CRP was then evaluated. Anti-ghB, but not anti-ghA and anti-ghC autoantibodies, markedly inhibited C1q interaction with IgG as well as CRP. These results appear to suggest that the anti-ghB autoantibodies may partially induce acquired functional C1q deficiency and thus may interfere with the biological function of C1q.     

Suppressor cells in common variable hypogammaglobulinemia with SRBC receptors and surface immunoglobulin

Common variable hypogammaglobulinemia (CVH) or adult-onset agammaglobulinemia is an acquired humoral immune deficiency characterized by low levels of circulating IgG, IgA, and usually IgM, frequent sinopulmonary infections and commonly, gastrointestinal tract infections. Although its place in the pathogenesis of this disease is unclear, a portion of patients with CVH have circulating suppressor T-lymphocytes capable of inhibiting immunoglobulin synthesis by B-lymphocytes of both the patient himself and normals with no humoral immune deficiency. In at least some situations, B-lymphocytes from such patients are capable of immunoglobulin synthesis when removed from the suppressor influences of their own T-cells. Although in mice surface antigens have been identified which are in varying degrees specific for suppressor cells, such cells have not yet been separated in humans. Although human T-lymphocytes with IgM Fc receptors have been characterized as helpers, while those with IgG Fc receptors as suppressors, there are experimental circumstances in which this division breaks down. We here describe a patient with common variable hypogammaglobulinemia with circulating suppressor cells whose unique surface characteristics enabled their physical separation.     

Clinical and immunological evaluation of patients with mild IgG1 deficiency.

Serum IgG subclass concentrations were determined in patients visiting, the pulmonology out-patient clinic with chronic respiratory tract problems. A total of 24 patients with a serum IgG1 concentration < 4.9 g/l (i.e. below the reference range) and normal values for IgG2, IgM and IgA were included. Patients with a selective IgG1 deficiency were vaccinated with a 23-valent pneumococcal polysaccharide vaccine. There were nine patients with a poor antibody response to pneumococcal capsular polysaccharide antigens. Responsiveness to protein antigens was intact in all patients. Patients with pneumonia showed a significantly lower anti-polysaccharide response in the IgG2 subclass than patients without pneumonia. Patients with recurrent sinusitis showed a significantly lower response in the IgA isotype after vaccination with pneumococcal polysaccharide vaccine compared with non-sinusitis patients. It can be concluded that patients with recurrent sinopulmonary infections and a mild IgG1 subclass deficiency have an impaired IgG1 anti-polysaccharide response, which can extend to decreased IgG2 and IgA anti-polysaccharide responses.     

Systemic antibody deficiency in patients without serum immunoglobulin deficiency or with selective IgA deficiency.

Serum IgG tetanus toxoid antibody (IgGTTab) concentrations were measured in patients with chronic chest infections or recurrent acute chest infections following immunization and compared with results obtained in a group of 43 controls. Apart from selective IgA deficiency in some patients, all had normal or high serum immunoglobulins. Using an enzyme linked immunosorbent assay (ELISA) for IgG TTab, antibody was present following one immunization in all controls who had previously been immunized and following two immunizations in those not previously immunized. Ninety-seven and a half per cent of controls had a serum antibody concentration of greater than 4 micrograms/ml. Following the same immunization schedule, eight of 45 (18%) patients with chronic chest infections and three of 11 (27%) patients with recurrent acute infections had a serum IgG TTab of less than 4 micrograms/ml. The three patients with a low IgG TTab concentration and recurrent acute infections all had selective IgA deficiency. Two of these patients have benefited from injections of normal human immunoglobulin. It is suggested that systemic antibody deficiency as a cause of chronic or recurrent respiratory tract infections cannot be excluded by measuring serum immunoglobulin concentrations alone and that it is of value to measure antibody responses following immunization.