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.

Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice.

In the present work, we have dissected the mechanisms responsible for the impaired humoral responses in aging. We found that there was a substantially higher level of Ab-forming cells in the spleens of aged mice than that of young controls. However, the number of high-affinity, class-switched Ab-forming cells was severely decreased in the spleen of aged mice. The accumulation of low-affinity IgM Ab-forming cells in the spleens of aged animals was not due to a deficiency in isotype switching because the number of total IgG1 splenic plasma cells was not significantly reduced. Remarkably, plasma cells of both low and high affinity were significantly diminished in the bone marrow of aged mice compared with that of young mice. The results from reconstitution experiments showed that aged bone marrow was less supportive for plasma cells derived from young splenic B cells. These findings suggest that humoral immune deficiency in aging results from at least two mechanisms: the inability to generate sufficient numbers of high-affinity Ab-forming cells, which is a result of diminished germinal center reaction, and the defective bone marrow environment that has diminished ability to support the selection and survival of long-term Ab-forming cells.

Chronic inflammatory demyelinating polyneuropathy associated with dysglobulinemia: a peripheral nerve biopsy study in 18 cases.

The possible occurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) in association with an identified dysglobulinemic status is recognized and a causal relationship between the two has been suggested. We had the opportunity to study 18 patients presenting with CIDP and dysglobulinemia. This was an IgG monoclonal gammopathy (IgG MG) in 8 cases, an IgM monoclonal gammopathy (IgM MG) in 8, an IgG-IgM biclonal gammopathy in 1 case and an IgM monoclonal cryoglobulinemia in another. A peripheral nerve biopsy specimen was available for all patients and the morphological findings in these specimens in the cases of CIDP with IgG MG or cryoglobulin did not differ from those without, whereas characteristic features were observed in the cases of CIDP with IgM MG and anti-myelin associated glycoprotein activity.

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.

Update on lymphoid interstitial pneumonitis.

Lymphoid interstitial pneumonitis (LIP) involves a clinicopathologic pattern of pulmonary disease characterized by diffuse interstitial reactive lymphoid infiltrates. In adults, it occurs most commonly in autoimmune diseases, such as Sjögren's syndrome (0.9% of these patients) and primary biliary cirrhosis, whereas in children it is usually seen in HIV infection. Dysproteinemias (hyper- and hypogammaglobulinemia) are found in more than 60% of patients. Children can show CD8-lymphocytosis in bronchoalveolar lavage fluid, lung tissue, peripheral blood, and salivary gland, associated with HLA-DR5 haplotype. Radiographically, most patients with LIP have reticulonodular infiltrates, with or without patchy areas of consolidation. CT scans can show both small nodular and ground glass patterns, patterns that are diagnostically nonspecific. Reduced lung volumes and diffusing capacities are consistent and sensitive indicators of disease in LIP. In an experimental model, diffusing capacity was the single most sensitive functional index of disease progression. Microscopically, LIP is part of a spectrum of pulmonary lymphoid proliferations, ranging from follicular bronchitis-bronchiolitis and pulmonary lymphoid hyperplasia (the latter in AIDS patients), proliferations largely limited to airways, to low-grade malignant lymphoma. These patterns may be difficult to differentiate from each other. It appears that LIP sometimes evolves to lymphoma; the frequency of this evolution is probably low but is difficult to assess because low-grade lymphomas may mimic LIP. A relatively high frequency of LIP patients have Epstein-Barr virus DNA in their lungs but not all patients with LIP show this finding, suggesting other possible etiologies.

[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.

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.

A familial case of hyper-IgM immunodeficiency.

A 22-year-old male was diagnosed as having immunodeficiency with hyper-IgM based upon recurrent pneumonia, marked elevation of serum IgM and markedly decreased level of IgG. IgG-or IgA-bearing B cells were not detected in peripheral blood while a number and a proportion of peripheral blood T lymphocytes were normal. Peripheral blood lymphocytes from this patient proliferated normally in response to T-independent and T-dependent B cell mitogens, and to T cell mitogens. Furthermore, the same type of dysgammaglobulinemia with increased IgM was found in the patient's father and brother. From these observations, it is suggested that it is a rare case of autosomal dominant or polygenal inheritance of hyper-IgM immunodeficiency.

[The value of biopsy of the accessory labial salivary glands for the diagnosis of amylosis]. / Intérêt de la biopsie des glandes salivaires accessoires labiales pour le diagnostic d'amylose.

Diagnosis of amyloidosis depends on the demonstration of amyloid deposits in biopsies using specific stains. Recently, in addition to classical biopsies (kidney, liver, gum, skin, rectal mucosa), labial salivary gland biopsy has been recommended as safe diagnostic method. In our recruitment, it allowed the fortuitous discovery of amyloidosis in three patients suffering from rheumatoid polyarthritis or spondylarthritis. In five other patients (2 cases of familial amyloidosis, 1 dysglobulinemia, 2 primary cardiac amyloidosis), biopsy was performed for systematic search of amyloidosis. In five of these eight cases, a sicca syndrome was associated with the salivary deposits. These deposits were stained with congo red viewed in polarized light and with T thioflavine. Besides, Wright's method allowed to know the AL or AA type of amyloidosis and thus to guide the treatment. On the whole, labial salivary gland biopsy is a highly sensitive method for diagnosis of primary and secondary amyloidosis.

Childhood eosinophilic fasciitis presenting as inflammatory polyarthritis and associated with selective IgA deficiency.

A 13 year old school boy presented with seronegative inflammatory polyarthritis after a flu-like illness. Four months later clinical features of eosinophilic fasciitis became apparent. After histological diagnosis treatment was started with prednisone 40 mg daily, with a good response. Routine investigations showed persistent selective IgA deficiency.

Clinical efficacy of intravenous immunoglobulin in patients with severe inflammatory chest disease and IgG3 subclass deficiency.

To investigate the efficacy of i.v. IgG treatment in pediatric patients with inflammatory lung disease, a prospective, controlled clinical trial was carried out over a 2-year study period. Patients were enrolled on the basis of severe clinical symptomatology. After 1 year of conventional treatment, the patients received 400 mg/kg per month of an i.v. IgG product containing only trace amounts of IgG3 in addition to their regular treatment throughout the second year. Significant clinical improvement, as documented by duration of hospital stay (first year 27.8 days, second year 4.9 days), use of antibiotics (132.8 versus 30.9 days) and use of steroids (21.4 versus 0.7 days) could be observed. Data obtained on a subgroup of patients with IgG3 deficiency were analysed separately. These results indicate that patients with severe chest disease who have IgG3 deficiency will also benefit from i.v. IgG treatment. The mode of action cannot be attributed to replacement of the respective isotypes, but is probably due to the effect of i.v. IgG in preventing repeated viral infections.

Frequencies of interleukin-5 mRNA-producing cells in healthy individuals and in immunoglobulin-deficient patients, measured by in situ hybridization.

Interleukin-5 (IL-5) has previously been demonstrated to enhance immunoglobulin synthesis, especially IgA. Thus, it could be hypothesized that a defect production of IL-5 may cause immunoglobulin deficiency. We have analysed the frequency of IL-5 mRNA-producing cells in healthy adults and in patients with common variable immunodeficiency or selective IgA deficiency. Unstimulated lymphocytes were rarely found to synthesize IL-5 as measured by in situ hybridization. However, pokeweed mitogen and several other activating ligands induced the synthesis of IL-5 mRNA in peripheral blood and spleen lymphocyte cultures. After pokeweed mitogen activation, the number of IL-5 mRNA-producing cells most often peaked on day 3 with a maximal frequency of around 1-2% of mononuclear cells. In a kinetic study we were unable to detect any peak frequency differences between healthy controls (mean 0.44%) and 20 patients (mean 0.58%). Thus, although IL-5 has been reported to be an important regulator of IgA synthesis, a defect production does not seem to be the underlying mechanism in human immunoglobulin deficiency.

Myelodysplastic syndrome with trisomy 8 in an adolescent with Fanconi anaemia and selective IgA deficiency.

We describe a patient with growth failure and multiple congenital anomalies characteristic of Fanconi anaemia, but without the classical feature of progressive bone marrow hypoplasia. Following treatment with growth hormone for a period of 8 years, he presented with myelodysplastic syndrome and a karyotypically abnormal clone in the bone marrow (47,XY,+8). The diagnosis of Fanconi anaemia was supported by the induction of abnormally high levels of characteristic chromosome aberrations in peripheral lymphocytes following exposure in vitro to the bifunctional alkylating agent mitomycin C. Immune function studies also identified a selective IgA deficiency. The relative importance of interacting constitutional and exogenous factors involved in the development of preleukaemia in this patient is discussed.

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.