[Malabsorption syndrome in partial immunoglobulin deficiency (IgA deficiency)].
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Adult↗
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IgA deficiency.
IgA deficiency, the most common primary immunodeficiency, is a very heterogeneous clinical disorder which may be associated with a variety of infections, allergies, autoimmune disorders, gastrointestinal diseases, and genetic disorders. The central phenotypic feature of this immunodeficiency is a B cell differentiation arrest, the extent of which may determine the clinical variability. Integrity of the immunoglobulin genes and their expression by immature B cells in affected individuals suggests an immunoregulatory basis for the B cell arrest. Genetic studies imply that a susceptibility gene in or near the major histocompatibility locus may predispose homozygous individuals to a spectrum of antibody deficiencies which may range from isolated IgA deficiency to panhypogammaglobulinemia. Essential cofactors in the pathogenesis of IgA deficiency include environmental factors, such as certain drugs and viral infections.
B-Lymphocytes↗
Genetics of IgA deficiency.
IgA deficiency is the most common humoral defect in man and results in an increased susceptibility to respiratory tract and gastrointestinal infections. Both clinical and genetic data support a close relationship with common variable immunodeficiency, a disease which involves not only IgA and IgG production, but also, in half of the patients, IgM. It is likely that the two disorders represent an allelic condition with a variable expression of a common gene defect which is thought to be involved in the regulation of immunoglobulin class switching. It is possible that a single, autosomally inherited gene with a limited penetrance is responsible for the development of both these defects.
Gene Expression Regulation↗
Altered expression of lymphocyte Fc alpha receptor in selective IgA deficiency and IgA nephropathy.
To study the expression of FcR specific for IgA (Fc alpha R) on human peripheral lymphocytes (PBL), PBL from normal donors were incubated with 300 to 500 micrograms/ml MOPC 315 IgA having anti-trinitrophenyl (TNP) antibody activity at 4 degrees C or 37 degrees C for 60 min. Under this condition, less than 2% of total cells could form rosettes with TNP-coated ox red blood cells (TNP-ORBC). When cultured with MOPC 315 IgA at 37 degrees C for 18 hr, however, there was a dose-dependent increase of the rosette-forming cells (RFC) binding TNP-ORBC. Because 15 to 20% of the total cells bound TNP-ORBC but not unsensitized ORBC, the rosette formation appeared to be due to the cytophilic binding of IgA to the cells. The binding of MOPC 315 IgA was competed by TEPC 15 IgA and human myeloma IgA, but not by murine myeloma proteins of other classes, indicating that the receptor is specific for IgA. Fc alpha R was induced on 15 to 20% of fractionated T and B cells, as well as on 15 to 18% of concanavalin A-(Con A) activated lymphocytes when cultured with IgA. The induction of the receptor was dependent on protein and RNA synthesis, but not on DNA synthesis as suggested by the sensitivity to metabolic inhibitors, such as mitomycin C, actinomycin D, puromycin, and cycloheximide. In five patients with selective IgA deficiency (serum IgA, 0 to 4 mg/dl), only 5.1% +/- 1.7 of PBL formed rosettes with TNP-ORBC after culture with MOPC 315 IgA, whereas 12.5% +/- 2.5 of PBL from normal donors (serum IgA, 90 to 330 mg/dl) formed rosettes. Fc alpha R was induced on more than 15% of the cells from these patients, however, when cultured with IgA in the presence of a conditioned medium obtained from mixed lymphocyte culture from two normal donors. The results suggested that the abnormality in the patients' PBL might be in the induction mechanism rather than in the number of precursor cells that could express Fc alpha R in the presence of IgA. On the other hand, Fc alpha R was induced on 10.4% +/- 1.5 of PBL from the patients with IgA nephropathy (serum IgA, 382 +/- 11 mg/dl) when they were incubated with IgA for 1 hr at 37 degrees C. Because Fc alpha R on normal PBL was not induced by 1 hr of incubation with IgA, it appeared that the receptor was already expressed in vivo on the cells of these patients.
Animals↗
[B lymphocytes of patients with complete IgA deficiency secrete IgA in response to interleukin 10].
We have previously shown that human B lymphocytes cultured in the CD40 system, composed of an anti-CD40 mAb presented by a CD32-transfected fibroblastic cell line, proliferate but do not secrete immunoglobulins (Igs). However, the addition of particles of Staphylococcus aureus Cowan (SAC) induces B cell to secrete considerable amounts of Igs even in the absence of exogenous cytokines (CD40/SAC system). Additionally, B lymphocytes cultured in the CD40 system in the presence of human IL-10, produce high level of IgM, IgG and IgA, which are further increased by addition of SAC. Here, we have studied the capacity of peripheral blood lymphocytes from patients with IgA deficiency (IgA-D) to secrete Igs, particularly IgA after CD40 triggering. Peripheral blood mononuclear cells (PBMNC) from IgA-D patients cultured in the CD40/SAC system produced IgM and IgG, but no IgA. The addition of IL-10 to the cultures, enhanced the production of IgM and IgG and most strikingly induced the production of high amounts of IgA. The addition of IL-10 to PBMNC from IgA-D patients activated through CD40 alone resulted in the production of IgA. Thus, IL-10 can remove the block in B cell differentiation and allows B cells from IgA-D patients to differentiate into IgA secreting cells.
Adult↗
Central MHC genes affect IgA levels in the human: reciprocal effects in IgA deficiency and IgA nephropathy.
This study investigates the hypothesis that alternative alleles of one or more genes in the central major histocompatibility complex (MHC) predispose carriers to IgA deficiency (IgAD) or IgA Nephropathy (IgAN). Australian caucasian IgAD, IgAN patients, and controls were typed at HLA loci, single nucleotide polymorphisms, and microsatellites in the MHC. Alleles of the D6S273 microsatellite exhibited strong associations with IgAD and IgAN. D6S273*129 and *139 were more frequent in IgAD and less frequent in IgAN patients than controls. The reverse was true for D6S273*133 and *131. Alleles of other microsatellites exhibited weak associations with IgAD or IgAN. D6S273*129 is found on the 65.1 ancestral haplotype [HLA-B14(65),DR1], which has been reported to be increased in IgAD, but the majority of IgAD patients with D6S273*129 did not have other alleles of the haplotype. D6S273*139 is characteristic of the 8.1 ancestral haplotype (HLA-A1,B8,DR3), which was common in IgAD and rare in IgAN patients. Further studies of the 8.1 haplotype in Australian, German and Spanish caucasian subjects revealed that HLA-DR3, in the absence of -B8, is not associated with IgAD. However -B8 is associated with IgAD in the absence of -DR3, consistent with a susceptibility locus in the central MHC. Provisional mapping within this region is discussed.
Australia↗
IgA deficiency in shar-pei dogs.
Two shar-pei puppies examined because of signs of sinopulmonary disease, one of which also had skin disease, had deficient IgA concentrations. Deficient serum IgA concentrations also were confirmed in 30 of 39 (76.9%) clinically normal adult dogs in two colonies of shar-peis. Both courses of disease--sinopulmonary signs and chronic skin disease and a benign clinical course--have been reported in human patients with IgA deficiency. Thus, the shar-pei might be an appropriate model for studying the immunopathology of IgA deficiency in man.
Animals↗
Transfusion management of an IgA deficient patient with anti-IgA and incidental correction of IgA deficiency after allogeneic bone marrow transplantation.
A patient with multiple myeloma was noted to have an IgA deficiency during investigation of a possible transfusion reaction due to IgA deficiency and anti-IgA. Because of the patient's age, otherwise good health, and early stage of disease, he was enrolled in a research treatment protocol that involved an allogeneic bone marrow transplant (BMT). The BMT successfully put the patient in complete remission from his multiple myeloma and corrected his IgA deficiency. Class-specific IgG anti-IgA antibody that had been identified prior to BMT was no longer detectable in his plasma. Anaphylactic transfusion reactions were successfully avoided by using a combination of IgA-deficient and washed blood components including the marrow graft, and IgA-reduced intravenous immunoglobulin.
Adult↗
IgG4 deficiency in IgA-deficient patients.
IgG subclass deficiency may be an important factor in the infection proneness of some IgA-deficient subjects. Although several studies on IgG subclass deficiency in IgA-deficient subjects have been reported, most have been unable to assess the incidence of IgG4 deficiency because the limitations of the assay methods used have often made a distinction between low normal and subnormal concentrations impossible. Having developed an enzyme-linked immunosorbent assay capable of measuring concentrations of all the IgG subclasses in healthy subjects of all ages and having established age-normal ranges for IgG subclasses using this assay, we measured IgG subclass concentrations in 73 IgA-deficient patients, the majority of whom were children with recurrent respiratory infections. The results showed that IgG4 deficiency occurred in 26% of the patients and was the most common IgG subclass deficiency found. IgG1, IgG2 and IgG3 deficiencies occurred, respectively, in 10, 12 and 8% of the patients. IgA-IgG4 deficiency occurred in 16% of the patients; IgA-IgG2-IgG4 in 4%; and IgG1-IgG2-IgG4, IgA-IgG1 and IgA-IgG2-IgG3 each occurred in 3%. Other subclass deficiencies or combinations of deficiencies were less frequent. Our results suggest that IgG4 deficiency even in the absence of IgG2 deficiency may be an important but hitherto largely unrecognized factor in infection proneness in some IgA-deficient patients.
Adolescent↗
IgA deficiency and drug induced IgA deficiency in rheumatoid arthritis.
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Adult↗
Molecular analysis of B-cell differentiation in selective or partial IgA deficiency.
Selective IgA deficiency is the most common form of primary immunodeficiency, the molecular basis of which is unknown. To investigate the cause of selective IgA deficiency, we examined what stage of B-cell differentiation was blocked. DNA and RNA were extracted from three Japanese patients with selective IgA deficiency and three with a partial IgA deficiency. In selective IgA deficiency patients, Ialpha germline transcript expression levels decreased and alpha circle transcripts were not detected. Stimulation with PMA and TGF-beta1 up-regulated Ialpha germline and alpha circle transcripts. In some patients, IgA secretion was induced by stimulation with anti-CD40, IL-4 and IL-10. In partial IgA deficiency patients, Ialpha germline, alpha circle transcripts and Calpha mature transcripts were detected in the absence of stimulation. Our findings suggest that the decreased expression level of Ialpha germline transcripts before a class switch might be critical for the pathogenesis of some patients with selective IgA deficiency. However, in patients with a partial IgA deficiency, B-cell differentiation might be disturbed after a class switch.
Adolescent↗
[IgA deficiency].
Selective IgA deficiency is the most common primary immunodeficiency, with a prevalence of approximately 1/600 in whites. Most subjects are asymptomatic but some may suffer from frequent respiratory and gastrointestinal infections. Patients who suffer from frequent infections usually have a defect in antibody responses toward polysaccharides, which is often associated with IgG2 deficiency. Genetic predisposition to develop IgA deficiency has been shown to be linked to at least one locus on 6p21. Some IgA-deficient patients are also prone to develop more severe immunodeficiency called common variable immunodeficiency, which is associated with decreased IgG and sometimes IgM production as well as partial T-cell defect. In a few cases, IgA deficiency may reveal a severe disease such as ataxia-telangiectasia. Selective IgA deficiency contraindicates immunoglobulin administration. Only the minority of IgA-deficient patients who develop severe or frequent infections in association with IgG2 deficiency or impaired antibody response are candidates for prophylactic intravenous immunoglobulin substitution. Immunoglobulin preparations containing particularly low amounts of IgA are required to avoid adverse effects related to anti-IgA alloantibodies.
Child↗
Familial clustering of selective IgA deficiency.
Serum IgA levels of 35 healthy IgA-deficient index cases, of their 180 first-degree relatives, and of 31 other family members were studied. IgA deficiency was detected in 7.2% of the first-degree relatives, which is significantly more than the 0.25% frequency of IgA deficiency in healthy Finnish blood donors. Subnormal serum IgA levels were found in additional 13 (7.2%) first-degree relatives. The familial clustering of IgA deficiency seemed to be controlled by multigenic factors. IgA-deficient persons and their family members were tested for antinuclear and antithyroid antibodies, for rheumatoid factor (by latex test) and for other anti-IgG antibodies (by Ripley test). Antibodies against bovine milk were also studied. The relatives of IgA-deficient persons did not have more of these antibodies than the controls. It is suggested that various serological abnormalities are a consequence of the IgA deficiency rather than of genetic defects per se.
Autoantibodies↗
[Selective IgA deficiency].
Selective IgA deficiency may be defined as an inborn state characterized by a decrease of serum IgA levels below 8 IU/1 (approximately 5 mg/dl) which may be associated with clinical symptoms of disease. The frequency of this condition in the general population varies between 1 : 400 and 1 : 3000 in different countries. Patients with defects of chromosome 18, ataxia teleangiectatica and with connatal rubella syndrome have a high incidence of IgA deficiency. Inspite of the decrease in circulating IgA there are B-lymphocytes containing IgA molecules in the peripheral blood. Thus it has been concluded that transformation of B-lymphocytes into IgA bearing plasmacells is stunted by another mechanism. While small amounts of IgA may be released by transformed plasmacells the capacity of B-lymphocytes to mature into fully functioning plasmacells releasing normal amounts of IgA is defective. T-cells acting as suppressor cells for IgA differentiation have been demonstrated in peripheral blood and are a possible explanation for this phenomenon. The majority of individuals with IgA deficiency are healthy. Evaluations of increased susceptibility for infections have to consider the fact that 6 respiratory tract infections per year are the average for any preschool child. However a number of children with IgA deficiency suffer from recurrent bacterial infections such as sinusitis, bronchitis and pneumonia, usually responding well to antibiotic treatment. IgA deficiency has an established correlation with atopic disease. There is an 40 fold increase in incidence of allergies and autoimmune diseases such as rheumatoid arthritis, lupus erythematodes and thyroiditis in individuals with IgA deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
Autoimmune Diseases↗
[Immunoglobulin deficiency, special IgA deficiency in disorders of the gastrointestinal tract].
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Agammaglobulinemia↗
Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency.
BACKGROUND: IgA serum autoantibodies against tissue transglutaminase (tTG) have an established diagnostic value in coeliac disease, and high efficacy tests are widely available for their detection. However, serological evaluation of IgA deficient subjects is still difficult. AIMS: To evaluate the diagnostic potential of IgG class anti-tTG autoantibodies measured quantitatively using an enzyme linked immunosorbent assay (ELISA) compared with immunofluorescent detection of coeliac autoantibodies. PATIENTS: We tested serum samples from 325 IgA deficient subjects, including 78 patients with coeliac disease, 73 disease controls, and 174 blood donors. METHODS: IgG antibodies against human recombinant tTG were measured with an ELISA. IgG antiendomysium antibodies (EMA) were assayed by indirect immunofluorescence on human jejunum and appendix sections. RESULTS: The IgG anti-tTG ELISA had a sensitivity of 98.7% and a specificity of 98.6%, and the correlation with IgG EMA titres was high (r(s)=0.91). One coeliac patient, initially negative in all autoantibody tests, displayed both IgG anti-tTG antibodies and IgG EMA during later gluten exposure. IgG anti-tTG antibodies and EMA titres showed significant decreases (p<0.001) in treated patients. The frequency of IgG anti-tTG autoantibody positivity was 9.8% among IgA deficient blood donors and 11 of the 12 positive subjects with known HLA-DQ haplotypes carried DQ2 or DQ8 alleles. CONCLUSIONS: IgG anti-tTG and IgG EMA autoantibody tests are highly efficient in detecting coeliac disease in IgA deficient patients. The high prevalence of coeliac antibodies among symptom free IgA deficient blood donors who also carry coeliac-type HLA-DQ genes indicates that all IgA deficient persons should be evaluated for coeliac disease.
Autoantibodies↗
IgA synthesis by peripheral blood mononuclear cells from normal and selectively IgA deficient subjects.
IgA secretion and intracellular IgA synthesis by PWM-stimulated peripheral blood lymphocytes from normal and IgA deficient subjects were measured by radioimmunoassay. Cultured lymphocytes from eleven out of twelve IgA deficient subjects had impaired or undetectable IgA production. Measurement of intracellular IgA showed that the defect was more basic than simply defective secretion by IgA plasma cells. Co-culture of lymphocytes from IgA deficient and normal subjects revealed defects in both the B and T cell populations of IgA deficient subjects. In one subject the defect was in the T cells, in another the B cells, and in two others both T and B cells were defective.
Animals↗
Hypothesis: interleukin-5 production impairment can be a key point in the pathogenesis of the MHC-linked selective IgA deficiency.
Selective IgA deficiency (IgA-D) is associated with the expression of some human leukocyte antigens (HLA) haplotypes and Major Hystocompatibility Complex (MHC) gene products have been suggested to be involved in the regulation of IgA synthesis. Recently, we have obtained evidences indicating that MHC influences the production of IgA and interleukin-5 (IL-5) both in humans and in mice. Lymphnode cells from pychril chloride (PC1) immunised BALB/c mice (bearing the H-2d haplotype) fail to produce IL-5 when stimulated in vitro with PC1 and this correlates with low antigen specific IgA production in vivo. In contrast using congenic BALB/k mice (bearing the H-2k haplotype) an high production both of IL-5 and of PC1-specific IgA is observed. Moreover, in vivo or in vitro administration of IL-5 to BALB/c mice was able to increase the production of antigen specific IgA. Similar evidences have been obtained by evaluation of the HLA influence on circulating immunoglobulin levels and interleukin production in normal HLA typed subjects. In fact HLA-B8, DR3 positive subjects show reduced level of serum IgA and their peripheral blood mononuclear cells stimulated with mitogen produce significantly reduced amounts of IL-5, IL-12, IL-2 and Interferon-gamma. We hypothesise that HLA-B8, DR3 associated IgA deficiency, known to be asymptomatic, can be due to a lack of subsequent signals, in particular of IL-5, involved in the late regulation of B cell differentiation. Preliminary evidences demonstrating that low amounts of human recombinant IL-5 are able to reconstitute IgA production by cells from HLA-B8, DR3 IgA-D subjects, seem to confirm this hypothesis.
Animals↗