From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years.

The genetic investigation of a family presenting with a dominant form of hyper IgM syndrome published in 1963 and 1975 revealed a R190X nonsense mutation in activation-induced cytidine deaminase. This report illustrates the progress made over 6 decades in the characterization of primary immunodeficiencies, from immunochemistry to whole-exome sequencing.

Fatal neonatal-onset mitochondrial respiratory chain disease with T cell immunodeficiency.

We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporo-occipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes II+III and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8(+) T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8(+) T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease.

Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers.

Angioimmunoblastic T-cell lymphoma (or angioimmunoblastic lymphadenopathy with dysgammaglobulinemia [AILD]) was originally considered to be an abnormal immune reaction in which reactive follicles with germinal centers (GCs) are usually absent. When hyperplastic GCs are present along with an angioimmunoblastic reaction, the lesion has been interpreted as a benign hyperimmune reaction. We report seven patients with angioimmunoblastic T-cell lymphoma (AITL) who initially had hyperplastic GCs, shown to be malignant lymphoma by further studies and clinical follow-up. Clonal T-cell populations were observed in all specimens evaluated, and sequential biopsies showed histologic progression to typical AITL in two patients. Clinical presentation was characterized by generalized lymphadenopathy of acute onset, constitutional symptoms, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia in five patients; regional adenopathy preceded generalized adenopathy in two patients. Five patients had rapid progression of disease, and three patients whose treatment was delayed due to inadequate evidence to diagnose lymphoma died of infection. The initial biopsy findings of each patient were similar and showed angioimmunoblastic proliferation, hyperplastic GCs with ill-defined borders, and interfollicular tingible-body macrophages. These GCs differed from occasional residual follicles of typical AITL in that the GCs were enlarged and hyperplasia of follicular dendritic cells was not seen. Diagnostic clear cells were not observed. Apoptotic bodies were markedly increased and bcl-2+ lymphocytes were sparse compared with typical AITL. Results of in situ hybridization for Epstein-Barr virus were positive in each case. We conclude that hyperplastic germinal centers with ill-defined borders and frequent interfollicular tingible-body macrophages occur in a histologic variant of AITL that is necessary to recognize for early diagnosis and treatment.

A lactogenic-immune-deficiency-syndrome in cows: unexplained phenomenon.

The majority of adult cows in a certain dairy herd, were found to have very low levels of immunoglobulins (Igs) in their colostrum. This phenomenon was defined by us as Lactogenic-Immune-Deficiency-Syndrome (LIDS). The mean IgG levels were 44.5 and 57.2 mg ml-1 respectively (on two different occasions) as compared to that of a control group which was 103.4 mg ml-1. The levels of Igs in the colostra of heifers from the same herd were found to be higher than those of adult cows. The degree of LIDS was found to be closely related to the age of cows in the herd. The low levels of Igs in the colostra were not directly linked to their concentrations in the sera of the affected cows. The relatively low amount of IgA in the affected colostra suggests that the local production in the lymph tissue associated with the mammary glands is impaired as well. In order to investigate the etiology of the phenomenon, tests were carried out to reveal whether bovine leucosis virus (BLV) infection or immune complexes were involved in the pathogenesis of LIDS. The results were negative. The etiology of LIDS remains for the time being unknown.

The frequency of selective IgA deficiency in myasthenia gravis.

The frequency of selective IgA deficiency is unknown in myasthenia gravis. We screened a series of 333 consecutive adult myasthenic patients for selective IgA deficiency and found only one patient with a selective IgA deficiency, which is not significantly different from the normal population. Organ-specific autoimmune diseases may differ from systemic autoimmune diseases concerning their frequency of association with selective IgA deficiency.

Evidence for abnormally regulated alternative RNA processing of mu chain gene in B-lymphoblastoid cells from Bloom's syndrome.

Selective IgM deficiency is commonly found in patients with Bloom's syndrome. In this study, mu mRNA synthesis was investigated in B-lymphoblastoid cells transformed by Epstein-Barr virus (LCL) from a patient with Bloom's syndrome who showed selective IgM deficiency. LCL established from the patient with Bloom's syndrome well expressed IgM molecules in their surface, but scarcely produced secreted IgM, compared with healthy controls. The JH hybridization patterns of digested DNA of LCL from the patient with Bloom's syndrome showed the rearrangement of VDJ as well as those of control LCLs. The mu mRNA was well detected, but mu s C-terminal mRNA was poorly detected compared with control LCLs, indicating that secreted mu mRNA was poorly transcribed though membrane-bound mu mRNA was well transcribed. These results suggest that alternative RNA processing of mu chain gene is abnormally regulated in LCL from patients with Bloom's syndrome.

Deficiency of IgG subclasses and IgA, and elevation of IgE in children with a past history of bacterial meningitis.

Of 44 children who recovered from an attack of bacterial meningitis, 3 (7%) were found to have IgG subclass deficiency, 5 (11%) had IgA deficiency and 22 (50%) had raised IgE levels. These results suggest that immunoglobulin abnormalities may be an important predisposing factor in some cases of bacterial meningitis.

Human immunoglobulin G and immunoglobulin G subclasses: biochemical, genetic, and clinical aspects.

Human IgG consists of two identical heavy (H) chains and two identical light (L) chains joined by interchain disulfide bridges. Heterogeneity in the amino acid sequences of the H and L polypeptides results in at least three types of IgG variants at the structural and genetic levels. The four isotypic forms are IgG1, IgG2, IgG3, and IgG4, which share extensive homologies in the primary structure of their H chains. As a result, the subclasses cross-react antigenically, but they can be differentiated on the basis of subtle architectural dissimilarities. The biological and effector properties of the IgG isotypes have been associated, in part, with their structural differences. Genes determining the synthesis of human IgG heavy chains are located on chromosome 14. In several clinical situations the isotypes appear to be regulated or expressed in patterns reflecting the gene arrangement. The numeric designations of the subclasses correspond to the order of their proportional amounts in healthy adult serum: IgG1 greater than IgG2 greater than IgG3 greater than IgG4. Awareness of the importance of the roles of the four IgG isotypes in human health has steadily increased since they were first described in the 1960s. The recognition that deficits or increases in selected IgG subclasses may have clinical consequences has prompted considerable interest in quantifying the four isotypes in clinical specimens. In particular, deficiencies of IgG2, IgG3, and IgG4, singly or combined, are associated with chronic infections which may not be readily recognized in otherwise healthy people with normal serum total IgG concentrations. Different assay methods using polyclonal or monoclonal antisera with various calibrants have been applied; however, no standardized method exists at the present. IgG deficits are associated with gene defects and are acquired in secondary immunodeficiencies in conjunction with other disorders. IgG isotype selectivity has been recognized in autoimmune diseases and in response to carbohydrate and protein antigens derived from pathogenic microorganisms and common allergens.

Measurement of protein HC (alpha 1 microglobulin) and protein HC-IgA complex in different body fluids.

Protein HC and protein HC-IgA complex were measured in 18 different types of fluid sample from healthy subjects and patients with different illnesses to determine if the concentrations of protein HC and protein HC-IgA complexes could be used to monitor certain diseases, when measured separately. The normal values for HC ranged from between 0.30 mg/l in saliva and 11.7 mg/l in blood plasma. HC-IgA complex has a greater range, from undetectable concentrations (urine, colostrum, and cervical mucus) up to 59.2 mg/l in blood plasma. Undetectable concentrations of HC-IgA complex were also shown in serum from patients with IgA immune deficiency and in cerebrospinal fluid from patients with multiple sclerosis. Increased concentrations of HC were noted in bronchoalveolar fluid from a patient with pulmonary alveolar proteinosis, serum from patients with Behcet's syndrome, and in synovial fluid from patients with gout, chondrocalcinosis, and rheumatoid arthritis. On the other hand, the concentrations of HC-IgA complex were raised only in those patients with pulmonary alveolar proteinosis or rheumatoid arthritis.

[Behavior of immunoglobulin E in primary immunodeficiencies]. / Comportamiento de la inmunoglobulina E en inmunodeficiencias primarias.

The complexity of IgE synthesis and regulation is expressed in the IgE serum levels of 81 patients with primary immunodeficiency diseases. IgE serum levels were often elevated in patients with partial cellular deficiency and also in some with predominantly antibody defect, as isolated IgA and IgM deficiency. The lowest levels were found in the wider spectrum immunodeficiencies, such as the X-linked agammaglobulinemia and severe combined immunodeficiency. Due to the heterogeneity and variability of the immunological defects, even in these well defined immunodeficiency diseases, it is very difficult to establish a typical feature of IgE serum levels in these conditions.

Estudo dos níveis de eletrólitos no suor de imunodeficientes / Sweat electrolytes levels of immunodeficient patients

Os autores estudaram a concentraçäo de sódio e de cloro no suor de 14 pacientes imunodeficientes, 11 dos quais apresentavam deficiência seletiva de IgA. Em dois desses pacientes foram encontrados níveis alterados de eletrólitos no suor, näo sendo possível firmar o diagnóstico de mucoviscidose em nenhum deles. Os autores comentam as realaçöes entre imunodeficiências humorais e alteraçöes de eletrólitos no suor

Squamous cell carcinoma associated with disturbance of the IgA system.

A case of cell carcinoma of the skin associated with disturbance of the IgA system is described. Immunological observations revealed a marked low level of serum IgA and disturbance of the secretory IgA synthesis in the rectal mucosa. After the surgical removal of the skin tumor, the serum level of IgA was increased to half the normal-range level. The relationship of the disturbance of the IgA system to the occurrence of squamous cell carcinoma is discussed.

Selective IgA deficiency and circulating immune complexes containing bovine proteins in a child with chronic graft versus host disease.

We have previously shown that a selective absence of serum and secretory immunoglobulin A (IgA) may lead to the development of circulating immune complexes which appear to contain bovine milk antigens. We report here that high levels of circulating immune complexes were found in the serum of a child who was treated for severe combined immunodeficiency by bone marrow transplantation but in whom the IgA-producing cells subsequently failed. As increasing amounts of complexes appeared over a two year period, the child had a parallel progression of an apparent chronic graft versus host disease including a Sjögrens syndrome and scleroderma. Very large amounts of complexes were eventually formed but the level fell 77 per cent after milk was excluded from the diet. Chemical studies on the complexes showed that the majority of complexes did contain bovine milk proteins, and fluorescence antibody staining of skin biopsy samples showed the presence of dense deposits of bovine casein in the dermis. The relationship between bovine protein-antigen antibody complexes and the chronic graft reaction remains uncertain.

Synthesis of immunoglobulin and secretory component by gastrointestinal mucosa in patients with hypogammaglobulinaemia or IgA deficiency.

Biopsies of intestinal mucosa from patients with adult hypogammaglobulinaemia or selective IgA deficiency have been studied for the ability to synthesize immunoglobulins and secretory component. Tissue fragments were cultured in vitro in medium containing 14C-labelled amino acids and newly snythesized proteins were detected by radioimmunoelectrophoresis. Synthesis of IgA, and in some cases IgG and IgM, was found in intestinal mucosal biopsies from hypogammaglobulinaemics and IgA-deficient subjects. Biopsies from all the patients also synthesized secretory component, but evidence was obtained which indicated that secretory component does not combine normally with IgA. Tissue sections of these biopsies have also been studied by immunofluorescence and immunoglobulin bearing cells have been demonstrated. The present findings demonstrate that immunoglobulin synthesizing cells are present in the intestinal mucosa of immunoglobulin-deficient individuals. Local immunoglobulin synthesis may partially explain why these patients do not often have major problems with intestinal infections.