Hyper immunoglobulin M immunodeficiency. (Dysgammaglobulinemia). Presence of immunoglobulin M-secreting plasmacytoid cells in peripheral blood and failure of immunoglobulin M-immunoglobulin G switch in B-cell differentiation.

The peripheral blood lymphocytes of nine patients with hyper immunoglobulin (Ig)M immunodeficiency were studied in an attempt to define the cellular basis of this disorder. B cells were normal in number but qualitatively abnormal in all patients. Approximately one-half of the B cell consisted of small lymphocytes (7-9 mum in diameter) bearing surface IgM and IgD, as well as C3 receptors. These cells were driven to secrete IgM but not IgG after in vitro stimulation by pokeweed mitogen. In the blood there were also large lymphocytes (10-14 mum in diameter) that possessed surface as well as intracytoplasmic IgM but lacked C3 receptors. These cells spontaneously secreted large amounts of IgM in vitro and on electron microscopy were found to be rich in rough endoplasmic reticulum. Such a subpopulation of lymphoid cells was not detected in normal peripheral blood and was unique for all patients with hyper IgM immunodeficiency studied.T cells from all patients were normal in number and in function both in vivo and in vitro and were able to generate adequate T-cell help to support IgG synthesis by normal B cells. No evidence was obtained for T cells capable of suppressing normal IgG synthesis in any of the patients after coculture with normal peripheral blood lymphocytes. The defect in hyper IgM immunodeficiency is intrinsic to B cells, which fail to switch from IgM to IgG synthesis.

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.

Course of serum-Ig concentrations in B12 chickens of the UM line.

The University of Munich chicken line ("UM") is isogenic in respect to the MHC and divides into normogammaglobulinemic, permanent and transient dysgammaglobulinemic individuals. Hence the immune defect is independent of the MHC. Continual analysis of the immunoglobulins until the 50th week of life revealed: one group of dysgammaglobulinemic individuals showed an initial IgG peak between the third and sixth week of life. Unusually high IgM and IgA levels occur in permanent and transient dysgammaglobulinemic individuals previous to the appearance of the IgG deficit and previous to a possible initial IgG peak. These high levels remain throughout the life of the chicken, possibly due to a missing negative feedback mechanism. Transient dysgammaglobulinemic chickens also exhibited increased IgM and IgA values after IgG normalization. Based upon our results, we postulate that the dysgammaglobulinemia defect is already preprogrammed during late embryonic development. The prevalence of a B or T-cell defect is still under discussion.

IgA deficiency and systemic lupus erythematosus. Occurrence in an oriental woman with idiopathic epilepsy.

A 25-year-old Oriental woman developed systemic lupus erythematosus during a course of treatment with carbamazepine for long-standing idiopathic epilepsy. Serum IgA was virtually absent, while secretory IgA was quantitated in a small amount in the saliva and gastric juice. Results of immunofluorescent studies on the rectal mucosa and bone marrow did not show any IgA-producing plasma cells. Antibodies against IgA, IgM, milk protein, and bovine serum were detected in the serum. The ability to develop both circulating antibodies and delayed hypersensitivity against test antigens was suppressed. Enumerations of T lymphocytes and IgG and IgM B lymphocytes were within normal limits, whereas IgA B lymphocytes were decreased in number. Results of chromosomal analyses disclosed various abnormalities.

Uncompacted myelin lamellae in dysglobulinemic neuropathy.

Uncompacted lamellae, located preferentially in inner layers of myelin sheath, were observed in biopsied sural nerves of 3 cases of dysglobulinemic neuropathy, in which the main pathological findings of myelinated fibers were those of segmental demyelination and remyelination, and axonal degeneration with concurrent marked decrease of myelinated fiber density. The presence of uncompacted myelin lamellae is well explained by the irregular distribution of adaxonal, incisural and paranodal cytoplasm of the Schwann cell.

Unusual selective immunoglobulin deficiency in an Arabian foal.

A 10-month-old Arabian foal was evaluated for a suspected immunoglobulin (Ig) M deficiency. Decreased to nondetectable concentrations of IgM, IgA, and IgG (T), and a normal concentration of IgG, were present. Results of in vitro testing of the blood lymphocyte blastogenesis showed a weak response to the B-cell mitogen, lipopolysaccharide (LPS), but normal responses to T-cell mitogens. Results of postmortem examination showed synovitis of the left tibiotarsal and both scapulohumeral joints. Atrophy and edema of the lymph nodes and lymphocyte depletion in the thymus and spleen were seen. A subacute inflammatory infiltrate was observed in the kidney, synovium, liver, and brain. Etiologic agents were not identified. This case represents a previously unreported form of immunodeficiency disease in the horse.

Primary, severe, combined immunodeficiency disease of Arabian foals.

Set in a context of immunodeficiency diseases in general this paper provides a brief, illustrated review of a primary, severe, combined immunodeficiency (PSCID) disease of Arabian foals. Affected foals are clinically normal at birth but beginning at about 10 days of age they develop a range of clinical signs particularly bronchopneumonia and diarrhoea with which adenoviruses are peculiarly associated. Despite intensive therapy foals invariably die by about 3 months of age. Affected foals are profoundly lymphopagenic (greater than 1000 lymphcoytes per mm3). There is thymic and lymph node hypoplasia and all lymphoid tissues are profoundly depleted of both T and B lymphocytes. The depletion of both T and B lymphocytes suggests that the primary defect is at the level of bone marrow stem cells which are the precursor cells for both lymphocyte populations. PSCID of Arabian foals is inherited as a simple, autosomal, recessive gene. Some 2 to 3% of all such foals may be born with PSCID, this frequency corresponds to a gene frequency of about 30% in parents. The syndrome is, therefore, an important cause of economic wastage. It also represents the only occurrence of the syndrome in an animal species other than man and as such has considerable comparative interest.

[Ring-cell immunocytoma with polyneuropathy associated with dysgammaglobulinemia and amyloidosis]. / Immunocytom z prstencitých bunek s polyneuropatií pri dysgamaglobulinémii a amyloidóze.

Dysgammaglobulinemia, amyloidosis and generalization of tumour occurred step by step in sensomotoric polyneuropathy complicating a nonspecified malignant lymphoma. The tumor was specified later as a IgM lambda immunocytoma with substantial participation of signet ring cells. Their vacuoles were sometimes multivesicular and did not contain immunoglobulins. Final phase of the disease was characterized by nodular AL amyloidosis expressed especially in the lung, retroperitoneum and nervous system. Amyloidosis was connected with the vessel walls and their surroundings. Possible autoimmune pathogenesis of polyneuropathy as well as of immunocyte vacuolization were discussed.

Good Syndrome, a rare cause of refractory chronic diarrhea and recurrent pneumonia in a Chinese patient after thymectomy.

The diagnosis of Good syndrome is very difficult. It has various symptoms, and these symptoms can be present at different periods. In this report we present a patient with refractory chronic diarrhea, recurrent pneumonia, and dysgammaglobulinemia after thymectomy, who was finally then diagnosed with Good syndrome.

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.

Ultrastructural findings in the jejunal mucosa of children with IgA deficiency.

The primary aim of this work was to investigate the ultrastructural morphology of the small intestinal mucosa in children affected by selective IgA deficiency (SIgAD). Absorptive tests and intestinal biopsies were performed in a group of nine children with SIgAD, none of them presenting with diarrhea. Biopsy specimens were processed for routine histology and scanning or transmission electron microscopy (SEM and TEM). By light microscopy, the jejunal mucosa appeared normal in all but one patient with patchy villous atrophy. By SEM, two further biopsies showed small areas of flat mucosa surrounded by villous ridges of nearly normal height. By TEM, four out of the nine mucosal specimens showed degenerative changes of the surface epithelium, including enlargement of the mitochondria, apical accumulation of primary and secondary lysosomes, and shortening and branching of the microvilli. These findings suggest that the small intestinal mucosa of children with SIgAD often shows pathological changes, some of which are recognizable only at the ultrastructural level. The study of biopsy specimens by SEM seems to be a useful diagnostic tool when patchy mucosal damage may occur, as in some of our patients with SIgAD.

IgA-containing plasma cells in the intestinal mucosa of children with selective IgA deficiency.

In 8 children with selective IgA deficiency (serum IgA less than 5 mg/dl, secretory IgA less than 0.5 mg/dl in unstimulated saliva) immunofluorescent staining of intestinal biopsy specimens revealed the presence of IgA-containing plasma cells. This finding supports the hypothesis that in the intestinal mucosa of patients with IgA deficiency B lymphocytes undergo "sterile" differentiation into IgA-containing plasma cells probably incapable of secreting the IgA synthesized.

Immunohistochemical findings in the intestine of IgA-deficient persons: number of intraepithelial T lymphocytes is increased.

We studied jejunal biopsy specimens of 13 IgA-deficient persons (IgAdp) and 12 controls. Four Ig-Adp had celiac disease, in the others the jejunal mucosa appeared normal. Monoclonal antibodies and the peroxidase technique were used to identify T lymphocytes, T-lymphocyte subsets, HLA-DR antigens, and IgE-containing cells in the lamina propria and epithelium. Intraepithelial lymphocytes (IEL); goblet cells; and IgA-, IgG-, and IgM-containing cells were counted in paraffin sections. Both IgAdp with normal jejunal structure and IgAd celiacs on gluten-free diet (p less than 0.001 and p less than 0.01 versus controls, respectively) had decreased numbers of IgA-containing cells, and an increased number of IgM-containing cells (p less than 0.01) was noted in the IgAdp with normal jejunal structure. The IgAdp with normal intestines had increased numbers of intraepithelial lymphocytes (mean 57 cells/mm versus 33 in controls, p less than 0.01) and so did the IgAd celiacs after gluten challenge (mean 74, p less than 0.001). The HLA-DR antibody stained the epithelial cells of the IgAd celiacs differently from those of controls and IgAdp with normal intestines: the whole cytoplasm was never stained in the celiacs, but in six of 12 controls (p less than 0.05) and during gluten challenge, the crypt cells of the IgAd celiacs showed strong staining, never seen in a normal intestine (p less than 0.05 compared with pre-challenge specimens). The increase in IEL number in the jejunal mucosa of IgAdp probably indicates ineffective antigen exclusion.

[Bone histomorphometry in monoclonal dysglobinemia. Diagnostic and prognostic value]. / L'histomorphométrie osseuse dans les dysglobulinémies monoclonales. Intérêt diagnostique et pronostique.

Data of bony histomorphometry by transiliac biopsy were studied in 35 cases of multiple myeloma and 26 cases of benign monoclonal dysglobulinemia. In a first stage, the comparison between the two groups showed an osteoclastic resorption which was significantly higher in myeloma patients in osteolytic forms as well as asymptomatic forms, showing the diagnostic advantage of this measurement in these forms of the disease. Also, the association of a preservation of the bony trabecular volume with an osteoclastic hyper-resorption was only observed in myeloma patients. In a second stage, study of the evolution of myeloma patients permitted to demonstrate the pejorative prognostic value of an intense hyper-resorption (STRO greater than or equal to 6) from a vital point of view as well as the future of the bone; patients with an initial hyper-resorption develop an osteolysis during the first year and/or a hypercalcemia during the first 24 months; the search for a correlation between these parameters of bony resorption and known prognostic factors, has proven negative except for calcemia and the level of beta 2 serum microglobulins. This fact emphasizes the advantage of a treatment toward osteoclasts associated with the classic chemotherapy of multiple myeloma.