No evidence for prolonged excretion of polioviruses in persons with residual paralytic poliomyelitis in Ethiopia, Pakistan and Guatemala.

Persons who have developed acute flaccid paralysis following infection with wild-type polioviruses or vaccine-associated paralytic poliomyelitis usually excrete polioviruses for only a few weeks. However, some patients with paralytic poliomyelitis have had prolonged excretion of polioviruses for periods of up to 10 years after onset of disease. Most prolonged excretors have been identified in industrialized countries. We studied 348 patients 2-28 years old in Ethiopia, Pakistan and Guatemala with residual paralytic poliomyelitis to determine if they had IgA or IgG deficiency or persistent poliomyelitis excretion at least 1 year after onset of disease. None of the 348 affected individuals had IgG deficiency or persistent poliovirus excretion. One child had borderline low serum IgA concentration. Since we did not study children under 2 years of age, persons born with IgG deficiency disorders may have died in developing countries where replacement immunoglobulin therapy is not readily available. Nevertheless, persistent poliovirus excretion among persons 2 years of age and older with residual paralytic poliomyelitis is uncommon in developing countries.     

Hepatitis in Selective IgA Deficiency

Hepatitis occurred in five out of 12 patients with selective IgA deficiency who had been detected by immunelectrophoretic screening of 2,600 individuals. This apparent increased susceptibility to hepatitis has not been reported before, and it may be due to the defect in their local and humoral immune mechanisms.     

Gammaglobulin treatment and anti-IgA antibodies in IgA-deficient patients.

Antibodies to IgA may cause severe anaphylactic reactions during blood transfusions. Tests for anti-IgA antibodies were carried out on six patients with IgA deficiency (five of whom also had hypogammaglobulinaemia) who had received continuous gammaglobullin treatment for chronic or recurrent infections for three to eight years. Three patients had minute amounts of IgA, and three had none (less than 0.01 microgram/ml). Only one patient had anti-IgA. Her antibody titre did not change during treatment. No patient had any untoward effects of treatment, which relieved the symptoms of infection in every case. IgA determinations should be performed by more accurate methods than radial immunodiffusion when evaluating the risks of giving gammaglobulin to patients with hypogammaglobulinaemia and IgA deficiency. Probably the stimulus provided by intramuscular gammaglobulin in such patients is insufficient for the formation of anti-IgA antibody.     

Lymphadenopathy and selective IgA deficiency.

Four men presented with unexplained lymphadenopathy. Three had a history of recurrent respiratory infections for several years, and two had lymph node or hepatic granulomas. None was noted to have symptoms of immunodeficiency at the time of presentation. In one patient routine direct immunofluorescence study failed to detect IgA, and immunological investigations were therefore conducted in the rest. In all patients the findings were similar and characterised by a severe deficiency of IgA. In the absence of a more serious cause selective IgA deficiency may be enough to explain "idiopathic" lymphadenopathy.     

Case report. Cervical carcinoma with selective IgA deficiency

A patient with cervical carcinoma was found to have selective IgA deficiency. The intact cell-mediated immunity, normal levels of IgG and IgM, and the absence of serum and salivary IgA established the diagnosis. Contrary to those of normal persons, salivary IgM was elevated and salivary IgA was not detectable in this patient. The patient had no signs attributable to IgA deficiency, but she always had dryness of the mouth. The association between cervical carcinoma and selective IgA deficiency was discussed.     

Case report: Immunoglobulin A deficiency in patients with juvenile rheumatoid arthritis treated with aspirin

In three patients with juvenile rheumatoid arthritis, serum IgA concentrations were within the normal limit at the onset of disease and before aspirin administration. After aspirin administration, their serum IgA levels gradually decreased. After discontinuation of aspirin, their serum IgA levels gradually increased. These results suggest that IgA deficiency may be due to aspirin administration in such patients. The IgA production in vitro of peripheral blood mononuclear cells from a patient taken 3 months of discontinuation of aspirin was markedly inhibited by preincubation with aspirin. Since the patients' serum IgG and IgM levels hardly changed the heavy chain class switching may be influenced by aspirin through some undefined mechanisms.Abbreviations CH heavy chain constant region - ³H-TdR ³H-thymidine - Hepes N-2-hydroxyethyl-piperazine-N-2-ethanesulfonic acid - JRA juvenile rheumatoid arthritis - MEM minimum essential medium - PBMCs peripheral blood mononuclear cells - PBS phosphate buffered saline - PFCs plaque forming cells - PWM pokeweed mitogen - SI stimulation index     

Directional dominance for low IgM and IgA levels.

A biometrical genetical analysis of IgG, IgM, and IgA levels in 134 sets of twins is reported. High heritabilities, around .8, are found for all three immunoglobulin levels, and possible reasons for lower heritabilities found in family studies are discussed. There is evidence for genetical dominance tending to decrease IgM and IgA levels, but there is no evidence for the importance of family environment although the presence of dominance may make its detection difficult. The causes of covariation in the three measurements are unclear in males but in females appear to be mainly environmental in correlations with IgA and equally genetical and environmental in the IgG-IgM correlation.     

Islet-cell,thyroid, and gastric autoantibodies in diabetic identical twins.

Sera from 54 pairs of identical twins, 29 discordant and 25 concordant for insulin-dependent diabetes, and 11 pairs of concordant non-insulin dependent identical twins were examined for pancreatic islet-cell antibodies (ICAs). ICAs were found in 10 of the 29 diabetic discordant and eight of the 50 concordant twins (difference not significant P greater than 0-05). Six out of nine twins tested within one year of onset of diabetes were positive, whereas nine out of 29 tested after one to 10 years and three out of 41 tested after 10 years were positive. Only one of the 22 non-insulin-dependent twins had ICAs. Repeat ICA testing in five pair of insulin-dependent twins and in the siblings of one pair showed that ICAs may be present in people with normal glucose tolerance'' may precede clinical diabetes by several years; and may decline in titre or disappear with increasing duration of disease. Thyroid or gastric autoantibodies, or both, were found in 36 out of 108 insulin-dependent twins and three out of 22 non-insulin dependent twins (difference not significant P less than 0-05). Only four twins had both ICAs and thyrogastric antibodies. There were no significant associations between autoantibodies and HLA histocompatibility types. As ICAs are more common in the diabetic than the non-diabetic twins of the discordant pairs they must be associated with juvenile onset diabetes. ICAs may appear some years before the onset of diabetes, but their prevalence declines with increasing duration of diabetes. The factors determining the production of ICA differ from those for thyroid and gastric autoantibodies.     

Inheritance of quantitative expression of erythrocyte glucose-6-phosphate dehydrogenase activity in the Negro—a twin study

Studies have been conducted on eight sets of monozygous and nine sets of dizygous female Negro twins, both members of whom were heterozygous for G-6-PD deficiency. Twins were studied both by assay of erythrocytic G-6-PD activity and by the methemoglobin elution test (MET). The MET is a procedure which identifies histochemically cells with appreciable G-6-PD activity and permits accurate determination of the percentage of such cells in heterozygotes. Monozygous twins showed significantly less within-pair variation than dizygous twins with both the MET and G-6-PD assay.Concerning the significantly greater agreement in MET results in monozygous twins than dizygous twins, our present working hypothesis is that X-chromosomal inactivation in the Negro female is genetically controlled, rather than random. However, certain alternate hypotheses allowing for random X-inactivation have not been excluded; these include somatic cell selection after random X-inactivation, and cell exchange between identical twins in utero/it. Studies in nontwin related heterozygotes now underway should help differentiate among these various possibilities.In addition to the studies on 17 pairs of female twins heterozygous for G-6-PD deficiency, 26 pairs of nondeficient female Negro twins have been studied by G-6-PD assay. Within-pair variation in monozygous twins was significantly less than within-pair variation in dizygous twins in all cases. The genetic influences detected with the G-6-PD assay in the female twins could theoretically be due to nonrandom X-inactivation, to genetically determined quantitative differences in enzyme activity (e.g., isoalleles), or to both. By appropriate calculations, based on the MET results, we have factored out the effects of X-inactivation on overall enzyme activity in the heterozygous deficient twins. After removal of the effect of X-inactivation, monozygous twins heterozygous for enzyme deficiency continue to show significantly less within-pair variation than dizygous twins. This finding indicates significant genetic influences on quantitative G-6-PD activity other than X-inactivation and other than the deficiency allele. This conclusion has been strengthened by studies on male twins where X-inactivation is not present.Supported by USPHS research grants AM-09381, HE-17544, AM-09919, and HE-03341, by USPHS Career Development Award 1-K3-AM-7959 (Dr. Brewer) and by U.S.A.E.C. Contract (11-1)-1552.     

Cows' milk protein intolerance: a possible association with gastroenteritis,lactose intolerance,and IgA deficiency.

Twenty-five children with cows'' milk protein intolerance were studied. Twenty had presented with an illness clinically indistinguishable from infantile gastroenteritis; an enteropathogenic Escherichia coli was isolated from the stools in two children, and in six another member of the family simultaneously developed acute diarrhoea and vomiting. Twenty-three children had lactose intolerance secondary to cows'' milk protein intolerance. Eight out of 20 children were found to be partially IgA deficient. An acute attack of gastroenteritis, in damaging the small mucosa, may act as a triggering mechanism in cows'' milk protein intolerance, and a deficiency in IgA may be a predisposing factor in so far as it allows the patient to become sensitised to foreign protein.     

Immunoglobulin secreting cells in lymphocytes of patients with IgA deficiency or hyper-IgA

To assess the ability of immunoglobulin production in vivo, we enumerated the immunoglobulin secreting cells in the peripheral blood of patients with an IgA deficiency and of those with hyper-IgAemia. All seven patients with primary IgA deficiency and two of the three patients with secondary IgA deficiency had low numbers of IgA secreting cells. In all five patients with hyper-IgA the number of IgA secreting cells was increased. Our results suggest that measurement of immunoglobulin secreting cells in PBMCs is useful in the assessment of ability of immunoglobulin production in vivo.Abbreviations PBMCs peripheral blood mononuclear cells - MEM minimum essential medium - PFC plaque forming cells - VH immunoglobulin heavy chain variable region - CH immunoglobulin heavy chain constant region     

Cytokines Alter IgA1 O-Glycosylation by Dysregulating C1GalT1 and ST6GalNAc-II Enzymes

IgA nephropathy (IgAN), the most common primary glomerulonephritis, is characterized by renal immunodeposits containing IgA1 with galactose-deficient O-glycans (Gd-IgA1). These immunodeposits originate from circulating immune complexes consisting of anti-glycan antibodies bound to Gd-IgA1. As clinical disease onset and activity of IgAN often coincide with mucosal infections and dysregulation of cytokines, we hypothesized that cytokines may affect IgA1 O-glycosylation. We used IgA1-secreting cells derived from the circulation of IgAN patients and healthy controls and assessed whether IgA1 O-glycosylation is altered by cytokines. Of the eight cytokines tested, only IL-6 and, to a lesser degree, IL-4 significantly increased galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for the cells from IgAN patients. These cytokines reduced galactosylation of the O-glycan substrate directly via decreased expression of the galactosyltransferase C1GalT1 and, indirectly, via increased expression of the sialyltransferase ST6GalNAc-II, which prevents galactosylation by C1GalT1. These findings were confirmed by siRNA knockdown of the corresponding genes and by in vitro enzyme reactions. In summary, IL-6 and IL-4 accentuated galactose deficiency of IgA1 via coordinated modulation of key glycosyltransferases. These data provide a mechanism explaining increased immune-complex formation and disease exacerbation during mucosal infections in IgAN patients.     

Serum immunoglobulin levels following allogeneic bone marrow transplantation

In order to study the posttransplant evolution of serum immunoglobulin levels, we measured serum IgG, IgA and IgM levels in 50 recipients of allogeneic bone marrow before transplantation and at different intervals thereafter (days 39, 120, 365 and 730). IgG and IgM levels were depressed for 1 year and IgA levels for 2 years posttransplant. Immunoglobulin deficiency was more severe and prolonged in patients with graft versus-host-disease. Hypogammaglobulinemia may contribute to the frequent infections observed in these patients, especially those with chronic graft-versus-host disease.     

Transfer factor therapy in a case of complex immunodeficiency

A young woman with unclassified complex immune deficiency disease characterized by relapsing skin ulcerations, greatly depressed cellular immunity, absent serum IgA, and inability to develop circulating antibodies to typhoid vaccine, was treated twice with the dialyzable transfer factor from normal persons. Following such therapy she showed clinical improvement and strong delayed skin sensitivity to Candida, streptokinase-streptodornase, and moderate, rather short-lived hypersensitivity to PPD. In addition, she could be sensitized to dinitrochlorobenzene and her leucocytes responded normally to phytohaemagglutinin; all these manifestions of cellular immunity had been absent prior to therapy. She acquired the capacity to develop anti-typhoid antibodies.These findings appear to indicate that dialyzable transfer factor not only transfers delayed-type hypersensitivities preexisting in the donor but is also able to remedy hitherto unspecific defects existing in certain forms of immune deficiency.     

Family studies of IgA deficiency

Seventeen immunoglobulin A (IgA)-deficient subjects and other members from 13 families were examined at HLA-A, B and DR, C4A, C4B, and Bf loci. Of the 29 independent haplotypes in the IgA-deficient: subjects, 22 included deletions, duplications, or defects at the C4 or 21-hydroxylase loci. It is suggested that there may be a gene regulating serum IgA concentrations in this same region of chromosome 6. Three main supratypes explain most of the previously reported tHLA associations with IgA deficiency. These are A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3, Bw65(14), C4A2, C4B1/2, BfS, and Bw57(17), C4A6, C4B1, BfS. All three are proposed to carry a gene for IgA deficiency, while other supratypes carrying the same B allele generally do not. Other supratypes possibly associated with IgA deficiency were also identified. A survey of about 150 individuals with at least 1 of the 3 main supratypes revealed only 2 IgA-deficient subjects, and these were among the 20 that had 2 of these supratypes. This suggests the possibility of a recessive mode of inheritance, with penetrance determined by another factor which is not major histocompatibility complex-linked. All the supratypes found in this group of IgA-deficient subjects would then carry the putative recessive allele for IgA deficiency.     

IgA deficiency during treatment of infantile hypothyroidism with thyroxine.

Serum IgA concentrations in five children with infantile hypothyroidism fell soon after the start of treatment with thyroxine. In one child the IgA concentration fell appreciably (to less than 0.01 g/1) and remained reduced; in the four others it returned to normal. IgM and IgG concentrations were roughly normal throughout. The deficiency in IgA concentrations may have been due to stimulation by thyroxine treatment of a T cell suppressor system that, in the original hypothyroid state, was less than normally active.     

Immunogenetic and ontogenetic studies of chickens with selective IgA deficiency and autoimmune thyroiditis

In addition to spontaneous hypothyroidism and autoimmune thyroiditis, chickens of the obese strain (OS) have a high incidence of selective IgA deficiency. Elevated levels of serum IgM also occur in many OS chickens. The IgA deficiency begins by 2 weeks, the age when hypothyroidism is developing. Like thyroiditis, a greater incidence of IgA deficiency was noted in OS birds homozygous for the B¹ allele than for the B⁴ allele of the major histocompatibility locus. Although IgA deficiency occurs in both sexes, it is found in a higher frequency in females than males (2:1). An abnormal ontogenesis of immunological competence may influence both traits.     

DISSIMILAR ALLERGIC DISEASE IN IDENTICAL TWINS—A Study of Psychosomatic Aspects

Identical twins with bronchial asthma were studied. One had the first attack of the disease in late adolescence, the other not until he was adult.Both were demonstrated by immunologic means to be sensitive to house dust and certain foods. Yet, of itself, the factor of exposure to a known allergen seemed not enough to precipitate clinical allergic reaction in either of them.It is believed that emotional stress is accompanied by physiologic changes which facilitate increased reactions to antigenic agents that in normal circumstances would not cause clinical disease.The twins were widely different with regard to emotional development and in their reaction to situations of stress. In both of them allergic manifestations were associated with periods of emotional conflict.The dissimilar clinical manifestations of allergy in these identical twins may be explained by differences in personality and therefore in reactions to stress situations.     

Biological warfare

Identical twins with bronchial asthma were studied. One had the first attack of the disease in late adolescence, the other not until he was adult. Both were demonstrated by immunologic means to be sensitive to house dust and certain foods. Yet, of itself, the factor of exposure to a known allergen seemed not enough to precipitate clinical allergic reaction in either of them. It is believed that emotional stress is accompanied by physiologic changes which facilitate increased reactions to antigenic agents that in normal circumstances would not cause clinical disease.The twins were widely different with regard to emotional development and in their reaction to situations of stress. In both of them allergic manifestations were associated with periods of emotional conflict.The dissimilar clinical manifestations of allergy in these identical twins may be explained by differences in personality and therefore in reactions to stress situations.     

The St. Thomas' UK Adult Twin Registry.

The Registry consists of nearly 10,000 monozygous and dizygous adult caucasian twins aged 18-80 from all over the UK and was started in 1993. This is a volunteer sample recruited by successive media campaigns without selecting for particular diseases or traits. All twins receive a series of disease questionnaires. In addition over half the twins have been assessed in detail clinically for several hundred phenotypes related to common diseases or intermediate traits. The focus has been primarily on cardiovascular, metabolic, musculoskeletal, dermatological, and opthalmological diseases. Over 3000 DZ twins have had a genome wide scan performed as well as many candidate genes allowing both linkage and association studies. The registry has led to many successful innovative research projects, particularly in common diseases previously thought to be predominantly environmental and helped positionally clone some novel genes for common diseases.