Adenovirus hepatitis in a patient with severe combined immunodeficiency

An autopsy case of adenovirus hepatitis with severe combined immunodeficiency (SCID) is presented. A 7-month-old female was admitted to the Kitasato University Hospital with chief complaint of persistent fever. A diagnosis of severe combined immunodeficiency (SCID) was made because of defective function in both T and B lymphocytes. Respiratory disturbance and severe hepatic dysfunction were manifested after admission. She died of respiratory failure on the 40th hospital day. Autopsy findings revealed many focal necroses scattered irregularly throughout the liver. Degenerating hepatocytes around the focal necrosis contained nuclear inclusion bodies, and crystalline arrays of adenovirus virions were recognized in these cells by electron microscopy. Adenovirus antigens were brilliantly detected in the nuclear inclusion bodies by indirect immunofluorescence.     

Diagnosis of severe combined immunodeficiency

Early diagnosis of severe combined immunodeficiency (SCID) is important to enable prompt referral to a supraregional centre for bone marrow transplantation before the occurrence of end organ damage secondary to infective complications. This review outlines clinical, microbiological, and immunopathological clues that aid the diagnosis of SCID and emphasises the multidisciplinary approach needed to diagnose and treat these infants.     

Canine X-linked severe combined immunodeficiency

Our laboratory has identified and characterized an X-linked severe combined immunodeficiency (XSCID) in dogs that is due to mutations in the common gamma (γc) subunit of the interleukin-2 (IL2), IL4, IL7, IL9, and IL 15 receptors. Canine XSCID, unlike genetically engineered γc-deficient mice, has a clinical and immunologic phenotype virtually identical to human XSCID. It appears that speciesspecific differences exist in the role of the γc and its associated cytokines in mice compared to their role in humans and dogs, suggesting γc-deficient dogs may be a more relevant model for studing the role of the γc in humans. We are utilizing this model for a variety of studies to address:

1. Fundamental questions concerning the role of the γc in cytokine regulation and lymphocyte development.
2. The pathogenesis of XSCID.
3. Strategies for improving bone marrow transplantation outcome.
4. Development and evaluation of strateies for gene therapy.
5. Human hematopoietic stem cell development.

     

Lymphoid progenitor cells in severe combined immunodeficiency

In the present study we evaluated the possibility that patients with severe combined immunodeficiency (SCID) might be deficient in lymphoid progenitor cells in bone marrow. Bone marrow from six patients with SCID was studied for the presence of cells expressing antigens associated with the earliest known stages of lymphopoiesis—terminal transferase (Tdt), the common acute lymphocytic leukemia antigen (CALLA), and p24. Four of six patients had detectable Tdt⁺, CALLA⁺, and p24⁺ cells, although they were quantitatively reduced compared to results from normal infant marrow. In two of six patients no bone marrow mononuclear cells expressing any of these markers were detected. These two patients were more lymphopenic than the other four SCID patients. The absence or deficiency of Tdt⁺, CALLA⁺, and p24⁺ bone marrow cells in some patients with SCID (two of six in the present study) is consistent with the lymphopenia seen in these patients and suggests that the underlying defects which result in SCID affect the production of immature as well as more differentiated lymphocytes.Supported in part by National Institutes of Health Grants CA-21737 and CA-25097. Dr. Neudorf is the recipient of National Research Service Award CA-07180 from the NIH. Dr. Filipovich is the recipient of Clinical Investigator Award AM00989 from the NIAMDD.     

X-linked severe combined immunodeficiency in the dog

This study documents the occurrence of a form of X-linked severe combined immunodeficiency (SCID) in the dog with clinical, immunologic, and pathologic features similar to those of X-linked SCID with B cells in man. The disease in the dog is characterized by growth retardation and increased susceptibility to bacterial and viral infections in young pups. Affected pups have all died or were euthanatized by 5 months with signs of canine distemper, infectious hepatitis, or bacterial pneumonia. Laboratory findings include normal numbers of circulating B lymphocytes and normal concentrations of serum IgM, but low to absent concentrations of serum IgG and IgA, indicating a defect in the terminal differentiation of IgG and IgA B cells into immunoglobulin-secreting plasma cells. This is supported by the failure of peripheral lymphocytes to produce IgG or IgA plaque-forming cells in response to polyclonal activation. There are low-to-normal numbers of circulating T cells, but a severely depressed blastogenic response to T cell mitogens. Postmortem findings include thymic dysplasia and hypoplasia of lymphoid tissue. Family studies and breeding experiments are consistent with an X-linked recessive mode of inheritance.     

Adenosine deaminase deficiency in a child with severe combined immunodeficiency

A case is reported of an apparent total erythrocyte adenosine deaminase (ADA) deficiency in a girl suffering from severe combined immunodeficiency (c.i.d.). Four other erythrocyte enzymes investigated showed apparent normal activity. The ADA activity in erythrocytes from her parents was about half normal, suggesting that the girl had inherited a chromosome pair without information for normal red cell ADA-isoenzymes. The suspected chromosome deficit may have affected the ADA locus only, or it may involve a more extensive part of a chromosome including the ADA locus. In another child, a boy exhibiting clinically the same immunodeficiency syndrome, the ADA type and ADA activity were found to be normal. Recently, two other cases of lack of red cell ADA activity, both affecting girls with similar manifestations of immunological deficiency, have been reported from the U.S.A. (Giblett et al. 1972). These findings indicate that coexistence of a total lack of red cell ADA activity and some immunodeficiency syndromes may be a common condition.     

重症联合免疫缺陷病临床病理分析

目的探讨重症联合免疫缺陷病(severe combined immunodeficiency,SCID)的临床病理特征。方法对6例SCID合并全身性巨细胞病毒(cytomegalovirus,CMV)感染患者的临床资料及尸检结果进行分析。结果6例SCID均为男性,平均年龄4个月。主要表现发热、咳嗽、腹泻、抽搐,实验室生化及免疫学检查均异常。淋巴细胞绝对值显著降低,平均(0·5±0·16)×109/L,免疫球蛋白IgG、IgM、IgA均明显降低。尸检发现共同特点是胸腺体积、重量极小,平均1·5g。镜下胸腺皮髓质分界不清,淋巴细胞稀少或缺如,无胸腺小体形成;脾、阑尾、回肠淋巴组织稀少,浆细胞少见;合并全身性CMV感染侵犯几乎所有内脏器官。患儿因重症肺炎、呼吸衰竭致死。结论SCID早期确诊困难,多因严重、反复感染死亡。合并的CMV感染具有脏器累及广泛、常合并其他病原菌混合感染和中枢神经系统的易感性等特点。     

Pathomorphologic findings in severe combined immunodeficiency and reticular dysgenesia

Summary Pathomorphologic findings in an 11 month old boy with severe combined immunodeficiency (case 1) and in a 4 month old boy with reticular dysgenesia (case 2) are reported. Case 1: The bone marrow exhibited regular granule-, erythro- and thrombopoiesis. The hypoplastic thymus consisted exclusively of epithelial reticulum cells. The spleen and lymph nodes showed considerable depletion of lymphocytes in both the T- and B-cell areas. There was a complete lack of all lymphatic structures in the gastrointestinal tract and aplasia of the tonsils. Death resulted from Candida sepsis in conjunction with giant cell pneumonia closely resembling Hecht's pneumonia in measles. Case 2: The bone marrow showed a total lack of granulopoiesis. The strongly dysplastic thymus weighed only 1 g. The spleen, the lymph nodes and the gastrointestinal tract exhibited a very strange histologie structure resulting from a complete absence of lymphocytes and plasma cells. The tonsils were aplastic, the parathyroid glands as well as the other endocrine glands were normally developed. The cause of death was Klebsiella sepsis and Pneumocystis pneumonia, the latter without the characteristic interstitial plasma cell infiltration. The importance of the immune system for activation of the nonspecific mechanisms of defense is discussed with respect to the two types of immunodeficiency states described here.This paper was presented in part at the 6th Fall Meeting of the German Society for Pathology in Vienna, Oct. 11, 1975.     

Selective defect of a T helper subpopulation in severe combined immunodeficiency

The case of an infant female aged 1 month with severe infections, failure to thrive, and skin erythroderma is reported. Immunological studies demonstrated a severe combined immunodeficiency (SCID) with B cells and normal serum IgM levels. Studies of T-cell subpopulations showed a defect of a subset of T helper cells. Possible pathogenetic mechanisms are discussed.     

Defective membrane function in a patient with severe combined immunodeficiency disease

We report a girl with severe combined immunodeficiency with functional impairment of both humoral and cellular immunity despite normal numbers of B and T lymphocytes. Immunologic studies revealed hypergammaglobulinaemia, absent migratory response by polymorphonuclear leucocytes to chemoattractants, and diminished lymphocyte proliferative responses to mitogens, antigens and allogeneic leucocytes. However, stimulation of the patient's mononuclear leucocytes with the calcium ionophore, A23187, resulted in a normal proliferative response. We therefore postulate a membrane defect as the basis for immunologic dysfunction in this child.     

Monoclonal immunoglobulin-secreting lymphoma in a patient with severe combined immunodeficiency disease

A 3.5 year old boy with X-linked severe combined immunodeficiency disease (SCID), who had been in laminar flow isolation throughout his life, developed a B cell tumour producing up to 3008 mg/dl of an IgM kappa paraprotein 1 month after infusion of both liver and thymus cells from a fetal donor and 6 months after the last of six fetal liver cell infusions given over a 3 year period. Pretransplant studies revealed a high percentage of circulating B lymphocytes. HLA typing suggests that the tumour was of host origin.