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Intravenous immunoglobulin (IVIG) is sterilized and purified human plasma which contains supra-physiologic levels of immunoglobulin G. IVIG is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infectious diseases. Although numerous immunomodulatory mechanisms have been suggested, the exact mechanisms of action are poorly understood. There is also accumulating evidence that high-dose IVIG is efficacious in the treatment of some skin diseases, despite the lack of evidence from randomized, double-blind, placebo-controlled trials. Though in most cases, IVIG is only effective in combination with other immunomodulating strategies, it offers new hope for the treatment of many severe dermatologic conditions. This article focuses on the efficacy and safety of IVIG therapy in skin diseases.

Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV-infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment. The pathogenesis of HAD is mediated by disruption of neuronal cell signal pathways, which ultimately triggers neuronal apoptosis. Evidence indicates that a viral gene product, the transactivator of transcription protein (Tat), takes a responsive role to these events. We herein report that sulfated polymannuroguluronate (SPMG), a novel anti-acquired immunodeficiency syndrome drug candidate now in phase II clinical trial, significantly decreased vulnerability of PC12 cells to HIV Tat protein by protecting cells from apoptosis. Furthermore, SPMG potently arrested Tat-triggered PKCdelta and PKCtheta activation and blocked the downstream apoptosis signaling pathways mediated by both ERK1/2 and caspase-3. These molecular mechanisms were attributed to the fact that SPMG reduced Tat-evoked calcium overload. These data demonstrate that SPMG might serve as a valuable therapeutic intervention for Tat-induced neuronal cell death and the subsequent pathologic events of HAD.

INTRODUCTION There are different causes for knee joint effusions in children. Rheumatoid diseases and hematogenous septic arthritis are the most important differential diagnoses. It is less known that immunodeficiency syndromes may cause serous monarthritis. RESULTS A case of a five years old boy with monarthritis of the knee is presented. Blood assay and specific immunologic analysis revealed a so far unknown X-linked agammaglobulinemia (M. Bruton). CONCLUSIONS In case of a monarthritis in children the orthopaedic surgeon or the pediatrician is primarily involved. For differential diagnosis X-linked agammaglobulinemia should be considered as reason for monarthritis, especially, if there are other clues to that disease in the medical history. In the case of agammaglobulinemia effusion and swelling will decrease soon after treatment with intravenous gammaglobulin.

Pathology due to the immune system's response to viral infections often represents a delicate balance between inhibition of viral pathogenesis and regulation of protective immunity. In susceptible C57BL/6 (B6) mice, the murine retroviral isolate LP-BM5 induces splenomegaly, hypergammaglobulinemia, profound B- and T-cell immunodeficiency, and increased susceptibility to opportunistic pathogens and terminal B-cell lymphomas. Here, we report that B6.PD-1 (programmed death-1) and B6.IL-10 knockout mice are substantially more susceptible to LP-BM5-induced disease than wild-type B6 mice. LP-BM5-infected B6.PD-1−/−mice developed more severe splenomegaly, hypergammaglobulinemia, and immunodeficiency than infected B6 mice: PD-1−/−mice are more susceptible to lower doses of LP-BM5 and show more exaggerated disease early postinfection. LP-BM5-infected B6.IL-10−/−mice also develop exaggerated LP-BM5-induced disease, compared to B6 mice, without a significant change in the retroviral load. By reciprocal reconstitution experiments, comparing wild-type versus PD-1−/−sources of the requisite cells for LP-BM5 pathogenesis—CD4 T and B cells, PD-1+B cells appear to be crucial in the normal limitation of LP-BM5-induced disease in B6 mice. Also, infected B6 mice have increased CD11b+spleen cells that express interleukin-10 (IL-10). However, PD-1−/−mice, though showing an even greater expansion of CD11b+cells after LP-BM5 inoculation, did not show an equivalent increase in IL-10-producing cells. Thus, it appears that PD-1/PD-L interactions and IL-10 are primarily important in moderating the effects of LP-BM5-induced disease in B6 mice.

Since the discovery of the genetic basis of DOCK8 immunodeficiency syndrome (DIDS) in 2009, several hundred patients worldwide have been reported, validating and extending the initial clinical descriptions. Importantly, the beneficial role of hematopoietic stem cell transplantation for this disease has emerged, providing impetus for improved diagnosis. Additionally, several groups have further elucidated the biological functions of DOCK8 in the immune system that help explain disease pathogenesis. Here, we summarize these recent developments.

Umbilical cord blood (CB), as a source of hematopoietic stem and progenitor cells for hematopoietic reconstitution, has been used for over two decades in allogeneic transplantation to treat patients with hematological malignancies, bone marrow failure, immunodeficiency syndromes, hemoglobinopathies, and certain inherited metabolic disorders. CB banks have been established worldwide, and regulatory pathways for licensure of publicly banked units are in place in the USA and other countries around the world. CB is immunologically tolerant thereby expanding access to transplantation for patients unable to find a fully matched donor and, because of rapid availability, is also a unique option for treatment of children with otherwise lethal inherited metabolic diseases affecting the brain. CB is likely to be an important source of cells for use in the emerging fields of cellular therapies and regenerative medicine.

Human immunodeficiency virus (HIV) is a lentivirus which that may progress to immunodeficiency syndrome (AIDS) and predispose for opportunistic infections and malignancies. According to recent reports, 1.5 million people died of AIDS in 2013 worldwide which is a 35% decrease since 2005. The number of deaths has decreased in part due to antiretroviral treatment (ART) wide spread use. In Bahrain, in 2011, a multidisciplinary team was established for HIV management involving major stakeholders: public health, infectious diseases, pharmacists, nursing and virologists. A retrospective descriptive study is done about HIV positive patient in Bahrain, their current treatment regimens and other blood parameters were collected, aiming to have a general idea about their health status in a way to help in their medical care. The data was collected retrospectively from the 2014 registry about all patients who are diagnosed to have HIV. Their ART regimen, CD 4 count and viral load were gathered and entered in Excel sheet.. A total of 208 patients were diagnosed to have HIV up to 2014. However, only 108 of them have their full data. In addition, a review of the frequency of admission of these patients over a 10 year period was done too. On reviewing the medical records of the patients admitted over the last ten years from 2004 till 2014, it was found that the total admission of HIV positive patients were 107. Hepatitis C was the most common co infection among those patients with a percentage of 24%. It was found that with better ART treatment and better structure of HIV team and program, we are getting more patients to be controlled. There is a clear increase in the number of patients with improving CD4 count. Based on the results of our study, the HIV multi-disciplinary management team is an essential part for the best management of these patients.

Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus (HIV)-infected patients have several non-acquired immunodeficiency syndrome (AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus (HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.

Targeting specific inhibition of enzymes has become an important structure-based method for designing novel therapeutic agents. During the last two decades, 10 inhibitors of Human immunodeficiency virus (HIV)-1 protease have been approved by the FDA as anti-acquired immunodeficiency syndrome (AIDS) drugs, serving as examples of the success of this approach. This article provides information on the inhibitors of the HIV-1-encoded protease, with particular emphasis on those molecules that have been used as drugs that helped to change HIV-1 infection and AIDS from an invariably fatal disease to a manageable one.

Cellular DNA double-strand break-repair pathways have evolved to protect the integrity of the genome from a continual barrage of potentially detrimental insults. Inherited mutations in genes that control this process result in an inability to properly repair DNA damage, ultimately leading to developmental defects and also cancer predisposition. Here, we describe a patient with a previously undescribed syndrome, which we have termed RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties), whose cells lack an ability to recruit 53BP1 to sites of DNA double-strand breaks. As a consequence, cells derived from this patient exhibit a hypersensitivity to ionizing radiation, cell cycle checkpoint abnormalities, and impaired end-joining in the recombined switch regions. Sequencing of TP53BP1 and other genes known to regulate ionizing radiation-induced 53BP1 foci formation in this patient failed to detect any mutations. Therefore, these data indicate the existence of a DNA double-strand break-repair protein that functions upstream of 53BP1 and contributes to the normal development of the human immune system.

BACKGROUND Tuberculosis is the most frequent infectious disease causing death worldwide. The main risk factor is an HIV infection. CNS involvement occurs in 5 - 20 % of HIV infected patients with tuberculosis. MATERIAL AND METHODS We investigated all cases of CNS tuberculosis in HIV infection treated in a German university hospital from 1998 to 2006. Clinical symptoms, differential diagnosis, diagnostic and therapeutic standards of cerebral tuberculosis, including specific aspects in HIV infection, are discussed. RESULTS The incidence of CNS tuberculosis in HIV infected patients was 1.5 %. All patients were transiently treated in an ICU. Related to all HIV infected patients admitted to an ICU, the incidence of CNS tuberculosis was 10 %. CONCLUSIONS Tuberculosis is an important differential diagnosis in HIV infected patients with focal and diffuse brain lesions. Due to the HIV associated immunodeficiency syndrome, atypical diagnostic results are seen frequently. Extensive diagnostic investigations should be performed, including biopsy and search for extra cerebral manifestation. An antituberculous treatment is indicated even in cases suspicious of cerebral tuberculosis. HAART reduces the mortality risk significantly.

Background Pneumocystis jiroveci pneumonia occurs frequently in patients with immunodeficiency syndromes, especially AIDS. Approximately 5% of AIDS patients have atypical granulomatous histology. Case Report/Methods A 75-year-old woman with chronic lymphocytic leukemia was treated with alemtuzumab (campath-1H) 3 times weekly for 12 weeks. After completion of therapy she presented with dyspnea, hypoxemia, and bilateral infiltrates. Bronchoscopy with biopsy revealed Pneumocystis organisms with granulomatous history. She responded well to trimethoprim-sulfamethoxazole. Results/Literature Review Our literature review identified 19 patients without AIDS who had granulomatous Pneumocystis infection. These patients often had nodular infiltrates on x-rays and negative bronchoalveolar lavage study findings. Most patients required open lung biopsies. Histologic specimens frequently revealed necrosis. These patients responded well to therapy. Conclusion The limited information available from these studies suggests that these patients have immune reconstitution-like syndrome related to either increasing numbers of CD4 + lymphocytes following therapeutic suppression or impaired modulation of CD4 + function. This unusual clinical presentation may delay diagnosis and effective therapy.

Item does not contain fulltext We report on two sibs with ICF syndrome (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) diagnosed in the elder brother based on the typical chromosomal abnormalities present in 56% of metaphases from cultured lymphocytes. In a previous cytogenetic analysis this diagnosis had been missed due to low manifestation of the ICF chromosomal phenotype. Hypomethylation of classical satellites 2 and 3, and of alpha-satellite DNA was shown in the lymphocytes of the younger sister. At 7 years of age the boy presented with hemiplegia due to tumerous invasion of the right brachial plexus. Histopathology revealed classical Hodgkin lymphoma, a neoplasia which might have been facilitated by the underlying genetic defect.

This report presents the findings of a large spatial analysis of almost 3 million viral load tests from over 2 million HIV patients on antiretroviral therapy in South Africa. It is part of the second phase of a series of analytical and evaluation studies contributing to the design of an impact and process evaluation of South Africa’s National Adherence Guidelines for Chronic Diseases. The analysis was conducted by the National Health Laboratory Service (NHLS) and Boston University/Health Economics and Epidemiology Research Office (HE2RO), in collaboration with the National Institute for Communicable Diseases (NICD), the National Department of Health of South Africa, and the World Bank. A number of other institutions contributed in the multi-step process of creating a patient-linked cohort through a novel record linkage algorithm and a masterlist of public sector health facilities, which are both underpinning this analysis and described in the report. The analysis demonstrates the diversity in the proportion of HIV patients getting a viral load test annually and patients virally suppressed. The variation shows by geographic location and facility, as well as by age, gender and demography. It sheds light on high viral load levels in young HIV patients on treatment. Also, one in six male and one in nine female ART patients were identified as having a high risk of HIV transmission due to viral load levels above 10,000 copies/mL

Human immunodefiiency virus (HIV) infection and aquired immunodeficiency syndrome (AIDS) cause a progressive depletion of CD4+ T cell populations accompanied by progressive impairment of cellular immunity and increasing susceptibility to opportunistic infections. Seborrheic dermatitis is one of the most common skin opportunistic infections on HIV/AIDS patients. Malassezia species is bilieved as the causative of seborrheic dermatitis. The aim of the study was to evaluate low CD4+ T cell counts as risk factor for Malassezia sp. infection in HIV/AIDS patients. This was an observational study with cross-sectional design conducted on HIV/AIDS patients who attended in Department of Dermatology and Venereology, Faculty of Medicine Universitas Gadjah Mada/ Dr Sardjito General Hospital, Yogyakarta and met the inclusion and exclusion criteria. Culture of Malassezia sp. was conducted in Department of Microbiology and classified as high (>100 CFU/ tape) and low (200 cells/mm3) and low (60 years were involved in the study. The number of Malassezia sp. colony on subjects with high and low CD4+ T cell counts were 31.55 ± 26.21 and 25.2 ± 33.89 CFU/ tape, respectively. No significantly relationship between between CD4+ T cell count and Malassezia sp. colony number was observed in the study (p=0.607; 95%CI=0.04-5.19; RP=0.452). In conclusion, low CD4+ T cell counts is not risk factor for Malassezia sp. infection in HIV/AIDS patients.

Retroviruses are among the best studied viruses in last decades due to their pivotal involvement in cellular processes and, most importantly, in causing human diseases, most notably—acquired immunodeficiency syndrome (AIDS) that is triggered by human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2, respectively). Numerous studied were conducted to understand the involvement of the three cardinal retroviral enzymes, reverse transcriptase, integrase and protease, in the life cycle of the viruses. These studies have led to the development of many inhibitors of these enzymes as anti-retroviral specific drugs that are used for routine treatments of HIV/AIDS patients. Interestingly, a fourth virus-encoded enzyme, the deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is also found in several major retroviral groups. The presence and the importance of this enzyme to the life cycle of retroviruses were usually overlooked by most retrovirologists, although the occurrence of dUTPases, particularly in beta-retroviruses and in non-primate retroviruses, is known for more than 20 years. Only more recently, retroviral dUTPases were brought into the limelight and were shown in several cases to be essential for viral replication. Therefore, it is likely that future studies on this enzyme will advance our knowledge to a level that will allow designing novel, specific and potent anti-dUTPase drugs that are effective in combating retroviral diseases. The aim of this review is to give concise background information on dUTPases in general and to summarize the most relevant data on retroviral dUTPases and their involvement in the replication processes and pathogenicity of the viruses, as well as in possibly-associated human diseases.

Combined immunodeficiencies (CIDs) comprise a heterogeneous group of monogenic disorders manifesting with lymphocyte defects, recurrent infections and dysregulated immune response. Recently, we and others have described clinical and molecular features of the combined immunodeficiency syndromes

Tuberculosis is an infection highly prevalent worldwide, con-sidered to be a global health problem by the World Health Orga-nization. Currently, it is considered the most important commu-nicable disease in the world whose dissemination reaches acrossthe boundaries of developing countries. The number of tuberculo-sis cases has also been increasing in developed countries, mainlybecause of immigration between nations, as a consequence ofacquired immunodeficiency syndrome (AIDS), and also becauseof the utilization of immunosuppressive drugs. To give an idea aboutthe dissemination of such an infection, it is believed that one-halfof the world’s population has already had contact with the tu-bercle bacillus, and more than 10 million cases are diagnosedevery year

Combination antiretroviral therapy (cART) has transformed the outcome of human immunodeficiency virus-1 (HIV-1) infection from a severe immunodeficiency syndrome to a chronic clinically manageable disease. However, patients require lifelong therapy and are at risk of developing non-AIDS complications (1, 2). Despite viral suppression in patients on cART, HIV-1 persists via the establishment of a latent reservoir. The adverse aspects and burden of lifelong cART together with the establishment of HIV-1 latency substantiate the need for an HIV-1 cure. A cure will either require complete eradication of the latent HIV-1 reservoir (termed “sterilizing cure”), or a sufficient reduction of HIV-1 levels wherein long-term viral suppression can be achieved without cART (termed “functional cure”). A key barrier to an HIV-1 cure is the persistence of latent replication-competent HIV-1 within long-lived resting CD4+ T cells (3). Without active HIV-1 replication or antigen expression, these latently infected cells are hidden from cART and are not eliminated by immune responses.

One hundred and twenty-four patients (from 120 families) diagnosed as primary immunodeficiency diseases were enrolled from five tertiary medical centers. The distribution by an update eight categories showed 45 patients (13 females/32 males; 36.3%) with "predominant antibody deficiencies," 27 patients (6/21; 21.8%) with "T- and B-cell immunodeficiency," 25 patients (9/16; 20.2%) with "congenital defects of phagocyte," 25 patients (4/21; 20.2%) with "other well-defined immunodeficiency syndromes," one boy (0.8%) with "disease in immune deregulation" (Chediak-Higashi syndrome) and another with "complement 3 deficiency." None had "defects in innate immunity" or "auto inflammatory disorders." Pseudomonas and Salmonella spp. were the two most identified microorganisms in septicemia (39.7%; 27/68 episodes). Twenty-three patients (18.5%) had mortality. Stem cell transplantation succeeded in 7 of 12 patients. In addition to nine patients with DiGerge syndrome recognized by FISH, direct sequencing identified 12 unique mutations from 20 families, reflecting distinct Taiwan geography, although a selection bias may exist.

Disorders in immune function in lamas have been observed over the past years. However, it has been difficult to determine how many types of deficiencies exist. Through the use of flow cytometry and monoclonal antibodies specific for leukocyte differentiation molecules, it has been possible to characterize the immune system of lamas and determine the genetic basis of one disease, the juvenile lama immunodeficiency syndrome (JLIDS). The availability of monoclonal antibodies and flow cytometry now afford an opportunity to clinically diagnose animals with JLIDS at birth and characterize other immunodeficiencies in animals presenting with similar clinical signs of immune dysfunction. The findings also show that flow cytometry can be used to characterize disorders in other species.

The Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency syndrome caused by mutations in the WAS protein (WASP). This participates in signalling and cytoskeletal homoeostasis, and some of its activities are regulated by its binding to the WASP interacting protein (WIP). WIP deficiency, however, has not yet been shown to be of pathological significance in humans. Here we show that, in WIP null (WIP−/−) mice, it produces haematological alterations and anatomical abnormalities in several organs, most probably as a consequence of autoimmune attacks. Granulocytosis and severe lymphopenia are associated with a proportional increase in segmented cells and fewer bone marrow erythrocytes and lymphocytes. Splenomegaly is accompanied by an increase of haematopoietic tissue and red pulp, reduction of the white pulp, and fewer B (B220+) lymphocytes (also apparent in the lymph nodes and Peyer's patches). Ulcerative colitis, interstitial pneumonitis, glomerular nephropathy with IgA deposits, autoantibodies, and joint inflammation are also evident. These progressive immunological disorders closely mimic those seen in WAS. WIP deficiency may thus be implicated in some cases in which mutations in the gene encoding WASP are not detected. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Antiretroviral therapy (ART) has significantly reduced morbidity and increased life expectancy of individuals infected with human immunodeficiency virus (HIV). Consequently, non-acquired immunodeficiency syndrome (AIDS)-defining malignancies are increasing in frequency, which necessitates the concurrent use of antineoplastics and ART. Although drug interactions are a major concern when combining these agents, there is currently limited guidance on dose adjustments required to maintain safe and efficacious drug exposure.

The clinical and immunological data of 8 patients diagnosed with transient hypogammaglobulinemia of infancy (THI) are presented and compared to published data. All patients diagnosed with THI (recurrent sinopulmonary infections, serum immunoglobulins < −2 S.D. for the age, apparently normal cellular immunity, and absence of evidence of other immunodeficiency syndromes) and registered in the Pediatric Rheumatology and Immunology Clinic of Post Graduate Institute of Medical Education and Research, Chandigarh were included in the study. Eight patients were diagnosed with THI. Mean age of onset of symptoms was 5.5 (±2.9) months. All patients had low serum immunoglobulin G (IgG) concentrations at admission. In 3 of the 8 (42.8%) cases, the serum IgA and IgM concentrations were also low. Respiratory infections were the most common presenting complaint. All children received prophylactic cotrimoxazole. The mean follow-up period was 23.6 months (range 10–38 months). Seven of the 8 patients became asymptomatic dur...

To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity.Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5. Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed.(1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a 'negative ERG' indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of approximately 27.6-32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition.The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both antiretinal activity and RPE hypersensitivity. In this case, peripheral stem-cell transfusion with its associated chemotherapy failed to benefit the patient's vision; indications of autoimmunity appeared to increase following this treatment.

ICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromeric instability, and facial abnormalities. Mutations in the catalytic domain of DNMT3B, a gene encoding a de novo DNA methyltransferase, have been recognized in a subset of patients. ICF syndrome is a genetic disease directly related to a genomic methylation defect that mainly affects classical satellites 2 and 3, both components of constitutive heterochromatin. The variable incidence of DNMT3B mutations and the differential methylation defect of alpha satellites allow the identification of two types of patients, both showing an undermethylation of classical satellite DNA. This classification illustrates the specificity of the methylation process and raises questions about the genetic heterogeneity of the ICF syndrome.

Objective.—To review and update the literature on current trends with regard to Pneumocystis carinii (jiroveci ) diagnosis, treatment modalities, and its role in human disease processes. Data Sources.—Bibliographic databases (PubMed and Ovid) were searched for material and data between 1980 and September 2003 relevant to the review. Indexing terms used were “Pneumocystis carinii pneumonia,” and “Pneumocystis jiroveci,” with the English language as a constraint. Other sources were the PhD thesis of one of the authors (J.F.W., London University, 1993) and the library at the Arabian Gulf University in the Kingdom of Bahrain. Study Selection.—Acquired immunodeficiency syndrome and organ transplant cases with Pneumocystis carinii pneumonia. Data Extraction.—Independent extraction by 2 observers. Data Synthesis.—We reviewed the major characteristics of P carinii (jiroveci ) with special emphasis on the more recently acquired data including the presence of a round pore in the cyst wall, which appears to be used for the release of sporozoites, supporting the hypothesis of sexual reproduction in P carinii (jiroveci ). Conclusions.—Opportunistic infection with P carinii (jiroveci ) remains a significant cause of morbidity and mortality in human immunodeficiency virus and non-human immunodeficiency virus–associated immunosuppressed patients. Diagnosis may be achieved in the majority of cases by routine cytochemical stains and specialized techniques such as immunocytochemistry and polymerase chain reaction. The incidence of P carinii pneumonia can significantly be reduced with effective use of prophylaxis and early detection of cases at high risk. Immunization for P carinii pneumonia is in the early stages and presents a challenging area for research.

In the fifty years since Ogden Bruton discovered agammaglobulinemia, more than 100 additional immunodeficiency syndromes have been described. These disorders may involve one or more components of the immune system, including T, B, and NK lymphocytes; phagocytic cells; and complement proteins. Most are recessive traits, some of which are caused by mutations in genes on the X chromosome, others in genes on autosomal chromosomes. Until the past decade, there was little insight into the fundamental problems underlying a majority of these conditions. Many of the primary immunodeficiency diseases have now been mapped to specific chromosomal locations, and the fundamental biologic errors have been identified in more than 3 dozen. Within the past decade the molecular bases of 7 X-linked immunodeficiency disorders have been reported: X-linked immunodeficiency with Hyper IgM, X-linked lymphoproliferative disease, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency, the Wiskott-Aldrich syndrome, nuclear factor kappaB essential modulator (NEMO or IKKg), and the immune dysregulation polyendocrinopathy (IPEX) syndrome. The abnormal genes in X-linked chronic granulomatous disease (CGD) and properdin deficiency had been identified several years earlier. In addition, there are now many autosomal recessive immunodeficiencies for which the molecular bases have been discovered. These new advances will be reviewed, with particular emphasis on the pulmonary complications of some of these diseases. In some cases there are unique features of lung abnormalities in specific defects. Infections obviously account for most of these complications, but the host reaction to infection often leads to characteristic findings that can be helpful diagnostically. Finally, advances in treatment of the underlying diseases as well as their infectious complications will be covered.

Five neonatal Pallas' cats (Otocolobus manul) at the Oklahoma City Zoo died from toxoplasmosis with concurrent herpesvirus infection. These multiple infections suggested underlying immunodeficiency, perhaps caused by concurrent infection with feline immunodeficiency virus (FIV); so blood samples were collected for serology, serum protein electrophoresis, lymphocyte proliferation assays, and cytokine analysis by reverse transcriptase-quantitative competitive polymerase chain reaction (RT-qcPCR). Resulting data were compared with data from FIV-infected and control domestic short-haired cats. In addition, peripheral blood mononuclear cell cultures were propagated to detect FIV virus by both RT-qcPCR and detection of reverse transcriptase activity. Serum protein electrophoresis showed that four of six Pallas' cats had increased alpha, globulins. At least two Pallas' cats had decreased lymphoproliferation responses to mitogen. and all three tested animals exhibited defective interleukin-12 gene expression. Although these clinical and laboratory findings suggested an immunodeficiency syndrome, FIV infection could not be confirmed. On the basis of repeated blood test results, it can be concluded that nutritional, metabolic, or other systemic problems probably did not contribute to the disease syndrome. Further investigation of other possible causes of immunodeficiency, including a possible genetic component, in this population is needed.

The aim of this study was to evaluate the outcome of children undergoing treatment for malignancy and immunodeficiency syndromes in whom invasive pulmonary aspergillosis (IPA) developed.The authors reviewed the medical records of all patients treated at their institution from January 1990 to August 1999 for culture-proven pulmonary aspergillus infection.Among the 43 patients studied, the median age at the time of diagnosis of IPA was 13.1 years. The most common primary diagnoses were acute myelogenous leukemia (n = 18) and acute lymphoblastic leukemia (n = 14); 27 patients (63%) had received a bone marrow transplant (BMT). Of the 18 patients who underwent surgical intervention for IPA, 14 (78%) had one operation, whereas the remaining 4 patients had 2. The 4 patients alive at the time this report was written had undergone surgical intervention 2, 10, 23, and 44 months previously respectively. Surgical resection of the involved lung parenchyma was significantly prognostic for survival (P.001). Other factors that influenced outcome were the extent of pulmonary invasion, steroid use, and the timing of bone marrow transplantation (BMT) in regard to the diagnosis of IPA.The overall mortality rate of children treated for malignancies and immunodeficiency syndromes in who IPA develops remains high, and antifungal therapy alone may not be curative. Surgical resection may provide a small but possibly the only chance for survival. Therefore, we would advocate for resection of all involved tissue, even if it requires reoperation.

Fifty years ago a new disease, agammaglobulinaemia, was described. This was made possible by a great number of preceding technical innovations and theories on different fields of research, in particular haematology, microbiology/immunology and basic sciences. The widely used name "Bruton disease" credits one single man with a new observation which, however, was simultaneously made by several physicians. Agammaglobulinaemia was the first example of an immunodeficiency syndrome (IDS). Based on new facts, new ideas emerged which in turn gave rise to innovative research, concerning both clinical observations and basic problems. Many similar diseases, usually resulting from a genetic defect, were described. Since 1970, an International Committee appointed by the WHO, has, with periodic reassessments, been working on the classification of the syndromes. All participants of an efficient immune reaction can be deficient in individual patients, that is: antibodies, lymphocytes, phagocytes and complement. Basic scientists presented striking results concerning the structure and action of all elements mentioned above. Conclusion: mutual stimuli coming from observations in families and from gene technology have resulted in the elucidation of the genetic defects of most IDS. Recent results of genetic engineering seem to justify some hope for success in therapy.

Signal transduction by the B cell receptor (BCR) is an absolute requirement for the selection and development of B lymphocytes at multiple checkpoints. Binding to antigen via the BCR is complemented by a co-stimulus delivered through accessory and co-stimulatory cell surface molecules that regulate the signalling threshold. In addition, identification of genes associated with immunodeficiency syndromes has highlighted the importance of genetic regulation, particularly in immunoglobulin class-switching and somatic hypermutation. A 1-day symposium organised by the Biochemical Society considered some of the recent advances in our understanding of the molecules and regulatory pathways involved in B lymphocyte activation, differentiation and survival and the health consequences when threshold settings malfunction.

Introduction: Primary extranodal lymphoma (pENL), a type of Non-Hodgkin's lymphoma (NHL) are the group of malignant neoplasms that arise from tissues other than lymph nodes and alsofrom the sites devoid of normal lymphoid tissue. The incidence of extranodal lymphoma (ENL) has an increasing trend and it accounts for one-fourth of all NHL. Any anatomical site of the body can be source of origin for the ENL. The presence of distinct clinical features in many variants of pENL has varied etiology, some may be associated with microbial infection, immunodeficiency syndrome, auto-immune diseases etc. Case Report: We highlight case series of 13 patients presenting with pENL which we encountered in the span of three years. The diagnosis of these cases was made on histopathology and immunohistochemistry. Discussion: The term ENL encompasses a variety of morphological variants, molecular alterations, clinical presentations; thereby posing a diagnostic challenge. They require varied therapeutic approach due to organ specific problems. These cases are discussed in order to emphasize on the increased incidence of these primary extranodal lymphomas.

Patients with primary immunodeficiency are prone to persistently excrete Sabin-like virus after administration of live-attenuated oral polio vaccine and have an increased risk for vaccine-derived paralytic polio. We report a case of type 3 immunodeficiency-associated vaccine-derived poliovirus in a child in South Africa who was born with X-linked immunodeficiency syndrome.

Genetic identification of immunodeficiency syndromes has become more efficient with the availability of whole-exome sequencing, expediting the identification of relevant genes and complementing traditional linkage analysis and homozygosity mapping. New genes defects causing immunodeficiency include phophoglucomutase 3 (PGM3), cytidine 5′ triphosphate synthase 1 (CTPS1), nuclear factor κB–inducing kinase (NIK), cytotoxic T lymphocyte–associated antigen 4 (CTLA4), B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10), phosphoinositide-3 kinase regulatory subunit 1 (PIK3R1), IL21, and Jagunal homolog 1 (JAGN1). New case reports expanded the clinical spectrum of gene defects. For example, a specific recombination-activating gene 1 variant protein with partial recombinant activity might produce Omenn syndrome or a common variable immunodeficiency phenotype. Central and peripheral B-cell tolerance was investigated in patients with several primary immunodeficiencies, including common variable immunodeficiency and Wiskott-Aldrich syndrome, to explain the occurrence of autoimmunity and inflammatory disorders. The role of IL-12 and IL-15 in the enhancement of natural killer cell activity was reported. Newborn screening for T-cell deficiency is being implemented in more states and is achieving its goal of defining the true incidence of severe combined immunodeficiency and providing early treatment that offers the highest survival for these patients. Definitive treatment of severe immunodeficiency with both hematopoietic stem cell transplantation and gene therapy was reported to be successful, with increasing definition of conditions needed for optimal outcomes. Progress in HIV infection is directed toward the development of an effective vaccine and the eradication of hidden latent virus reservoirs.

Introduction Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against the postsynaptic nicotinic acetylcholine receptors, muscle-specific tyrosine kinase, low-density lipoprotein receptor-related protein 4, and agrin. The incidence of thymoma in MG is reported as ∼10%-15%. The incidence of extrathoracic metastatic thymoma is exceedingly rare and may present years after resection. Associations between thymoma and immunodeficiency have also been described, including Good syndrome. Methods and results We describe the clinical course, investigations, and treatments performed in a patient presenting with a myasthenic crisis in the setting of acetylcholine receptor antibody-positive generalized MG 10 years postthymectomy. Computed tomography imaging revealed 2 pancreatic lesions, but no residual thoracic thymoma. Biopsy confirmed metastatic pancreatic thymoma, which was successfully resected. His course was further complicated by cytomegalovirus retinitis with a depressed CD4 count and perniosis. Discussion This presentation was felt to be consistent with Good immunodeficiency syndrome.

Most central nervous system (CNS) pathogens infect the nervous system nonspecifically, and disease is the result of the brain's immune response. This is exemplified by viral and bacterial meningitis, which cause extensive inflammation of the brain or its coverings. However, some pathogens show neural tropism and specifically infect certain neurons, as illustrated by motor neuron infections underlying poliomyelitis, neurosyphilis, or infection of sensory neurons by herpes simplex. Similarly, infestation of the brain by larvae (cysticerci) from intestinal tapeworms nonspecifically causes neurological disease in millions of people in the developing world, whereas rare paralytic amoeba actively invade the brain through the nasal canal and feast on brain tissue. By far the most important neurological disease caused by a pathogen is neuro–acquired immunodeficiency syndrome (AIDS), the development of cognitive decline and dementia in the late stages of AIDS due to brain infection with human immunodeficiency virus. Given the magnitude of the global AIDS endemic, these cases will soon rival more traditional age-related dementia. Neuroscientists are unlikely to contribute to the development of more effective treatments, a task that rests on microbiologists and immunologists who to develop vaccines and antivirals. However, several neurotoxins (Botox) and neurotropic viruses (herpes simplex virus 1) are providing tools to treat neurological disease through targeted delivery of genes or paralytic therapeutics.

Common variable immunodeficiency (CVID) is a heterogeneous group of immunodeficiency syndromes that involves defective production of specific antibodies and decreased serum concentrations of > or =1 immunoglobulin isotype. We describe a patient with an atypical case of CVID who had extensive granulomatous lesions that were partially attributable to mycobacterial infection. In the peripheral blood, there was a massive increase in the number of double-negative CD3+ T cells that expressed the gammadelta T cell receptor.

Primary immunodeficiency disease can be broadly categorized into five groups encompassing: (a) combined immunodeficiencies; (b) primarily antibody deficiencies; (c) phagocyte disorders; (d) other well-defined immunodeficiency syndromes; and (e) complement deficiencies. Currently there are greater than 95 unique primary immunodeficiency diseases that fall into these five groups. The more common disorders in each of the first four groups will be reviewed in terms of: (a) individual diseases and their molecular etiologies; (b) diagnostic criteria that may include flow cytometry; and (c) our laboratory's own experience in the development and utilization of flow cytometry based assays for the diagnosis of primary immune deficiency disease including histograms of specific cases.

Glioblastoma of the brain stem is rare and there is no description of such a lesion in patients suffering from acquired immunodeficiency syndrome. The majority of intracerebral mass lesions are due either to toxoplasmosis or primary central nervous system lymphomas so that it is usually not included in the differential diagnosis of enhancing lesions of the central nervous system in these patients. A 31-year-old human immunodeficiency virus (HIV) infected man presented with a four months history of slowly progressive deterioration of brainstem associated symptoms despite antitoxoplasmic therapy. Magnetic resonance imaging revealed a large ring enhancing lesion in the brainstem. Clinical and neuroradiological data could not establish a proper diagnosis and a stereotactic serial biopsy was undertaken. Histological examination of the specimen showed a glioblastoma multiforme (GBM) as the first reported case of GBM located in the brainstem in an acquired immunodeficiency syndrome (AIDS) patient. Patient management and effectiveness of stereotactic serial biopsy are discussed.

Strong CD4 T cell activation and proliferation are seen in susceptible mice infected with the murine retroviral inoculum, LP-BM5, which produces an immunodeficiency syndrome called murine AIDS (MAIDS). We developed a short term adoptive transfer model of MAIDS to examine the requirements for the CD4 T cell response. Naive CD4 T cells from uninfected donors responded quickly after adoptive transfer into MAIDS-infected hosts, becoming activated and proliferating within several days. Using blocking mAbs to costimulatory ligands and CD4 T cells deficient in expression of their receptors, we found that the CD4 T cell response requires CD28:B7.1/B7.2 interactions, but not CTLA4 or CD40-CD40 ligand interactions. Naive CD4 T cells did not respond in H-2M-deficient mice with MAIDS, suggesting that disease requires recognition of self peptide-MHC complexes. The self MHC-dependent division and accumulation of large numbers of CD4 T cells suggest that MAIDS involves a disruption of the balance of homeostatic signals. Supporting this hypothesis, CD4 T cells from mice with MAIDS failed to regulate the homeostatic division of naive CD4 T cells in a cotransfer model. Thus, a combination of up-regulation of costimulatory ligands and disruption of homeostatic control may be responsible for CD4 lymphoproliferation in MAIDS.

Purpose Clinical course and autopsy findings in a patient with human immunodeficiency virus-1 immunodeficiency, central nervous system lymphoma, and bilateral, simultaneous ophthalmic artery occlusions. Design Observational case report. Methods Clinical examination, fundus photography, gross and microscopic pathologic study. Results Fundus photographs disclosed stasis in retinal arterioles, the absence of a cherry-red spot; internal carotid arteriography disclosed bilateral ophthalmic artery occlusions; postmortem histopathologic examination disclosed bilateral ophthalmic artery atherosclerosis, retinal ischemic necrosis, ischemic optic neuropathy, diffuse large-cell lymphoma of multiple areas of the central nervous system, cytomegalovirus encephalitis, atherosclerosis, and bronchopneumonia. Conclusions A 47-year-old male with aquired immunodeficiency syndrome, profound immunodeficiency, systemic hypertension, and central nervous system lymphoma, developed deep vein thrombosis, bilateral ophthalmic artery occlusions, and died of pneumonia 7 weeks after the onset of blindness. Postmortem study revealed bilateral ophthalmic artery hemorrhagic atherosclerosis, ischemic optic neuropathy, ischemic retinal necrosis, diffuse large-cell central nervous system lymphoma, cytomegalovirus encephalitis, pneumonitis, and systemic atherosclerosis.

Chemotherapy for tuberculosis in general and osteoarticular tuberculosis in particular poses certain peculiar problems that include chronicity of infection, infection by resistant mycobacteria, persistent mycobacteria, possibility of concomitant human immunodeficiency virus infection, and drug toxicity during prolonged treatment. Although the success rate of chemotherapy is greater than 90% with optimum drug combination regimens currently used, there is a need for additional improvement. A successful outcome depends on using an optimum regimen, which contains safer and more effective drugs given regularly for an adequate period. The most important cause of treatment failure is poor patient compliance, which can be improved by using supervised drug treatment programs. In a few patients, surgical removal of infected tissue may be indicated to improve the efficacy of chemotherapy. In the future, safer and more effective antimycobacterial and anti-acquired immunodeficiency syndrome drugs may become available. Research in various related fields also is expected to additionally improve prophylaxis and treatment.

This article reports the case of a 33-year-old woman with common variable immunodeficiency (CVI) who developed renal failure 17 years after diagnosis and initiation of treatment with monthly IVIG. A renal biopsy revealed mesangial and paramesangial immune complex deposition and interstitial granulomatous infiltration. Renal function improved with oral corticosteroids, but did not return to normal. Decreasing the dose of IVIG had no effect on renal function. Immune dysfunction can be associated with both granulomatous disease and immune complex glomerulonephritis, or the latter may be related to chronic infection or immunoglobulin use. This is the first report of concomitant glomerular-tubulointerstitial lesions in this immunodeficiency syndrome. Renal function should be closely followed in patients with CVI.

Protein loss via the gut can be caused by a number of gastrointestinal disorders, among which intestinal lymphangiectasia has been described to not only lead to a loss of proteins but also to a loss of lymphocytes, resembling secondary immunodeficiency. We are reporting on a 75-year-old female patient who came to our hospital because of a minor stroke. She had no history of serious infections. During the diagnostic work-up, we detected an apparent immunodeficiency syndrome associated with primary intestinal lymphangiectasia. Trying to characterize the alterations of the immune system, we not only found hypogammaglobulinemia and lymphopenia primarily affecting CD4+, and also CD8+ T cells, but also marked hypocomplementemia affecting levels of complement C4, C2, and C3. The loss of components of the immune system most likely was due to a chronic loss of immune cells and proteins via the intestinal lymphangiectasia, with levels of complement components following the pattern of protein electrophoresis. Thus, intestinal lymphangiectasia should not only be considered as a potential cause of secondary immune defects in an elderly patient, but can also be associated with additional hypocomplementemia.

CHS is a rare immunodeficiency syndrome with defects in the functions of cytotoxic cells and neutrophils. Approximately 85% of patients with CHS undergo an AP within the first decade, which is similar to FHLH. Chemotherapy could induce transient remission, but only allogeneic HCT could correct the underlying genetic defect and prevent relapse. We reported a case of CHS diagnosed at 19 months, who had an elder brother who had previously succumbed to the same disease. The little girl presented with severe AP manifestations including recurrent high fever, enlarged superficial lymph nodes, and extraordinary hepatosplenomegaly occupying the whole abdominal and pelvic cavity. Comprehensive therapies including HLH 2004 protocol, supportive care, and antibiotics, especially antituberculous agents, were given to her to induce remission. After remission, the patient received fully HLA-matched UCBT. The transplantation course was uneventful, except for fluctuation of donor chimerism. The patient has been alive for 36 months without infection and neurologic manifestations and is under further follow-up. Our result provides another case that UCBT can be effective for treating patients with CHS and remission before HCT is important for good prognosis.

A novel immunodeficiency syndrome has recently been defined in young adults. Known variously as dendritic cell, monocyte, B and NK lymphoid (DCML deficiency),[1][1] ‘autosomal dominant and sporadic monocytopenia’[2][2] or ‘MonoMAC’ (monocytopenia with Mycobacterium avium complex),[3][3] it

Genetic predisposition has been widely studied in autoimmune and autoinflammatory diseases and has been found to play a significant role in pathogenesis, although the environment, including dietary habits, chemicals and hygienic conditions have been postulated to influence expression of these diseases as well. The autoimmune diseases most prevalent in the newborn include neonatal lupus and neonatal antiphospholipid antibody syndrome. The diseases are characterised by maternal antibodies to SS-A (Ro) and SS-B (La). The genetics underlying these diseases have been found to involve both HLA and non-HLA associations. The neonatal autoinflammatory diseases include the cryopyrin-associated periodic syndromes (CAPS), of which familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multisystem inflammatory diseases (NOMID) are the three distinct phenotypes resulting from mutations in the CIAS 1 gene (NLRP3 gene). The gene mutation in CAPS are gain-of-function mutation of the NLRP3 gene coding for cryopyrin, resulting in dysfunctional inflammasomes. A defect in the inflammasome leads to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Understanding the genetics responsible for neonatal lupus, neonatal antiphospholipid antibody syndrome and CAPS may drive future research into an elucidation of complex pathophysiologic mechanisms of these diseases and perhaps ultimately lead to better treatment modalities. Key Concepts: Diseases that involve immune dysfunction in the neonate include neonatal autoimmune and autoinflammatory conditions, along with the more well-defined immunodeficiency syndromes. The genetics of neonatal autoimmunity and neonatal autoinflammatory syndromes are very different. In addition to a genetic component, the pathogenesis of these two groups of diseases may also involve an epigenetic and environmental component. The presence of a common genetic defect may result in different clinical phenotypes, as illustrated by the three CAPS syndromes. Treatment of these diseases is dependent on an increased knowledge of the pathogenesis of these diseases. Genetic counselling is an important component of the management of these diseases. Keywords: autoimmune disease; autoinflammatory disease; neonatal lupus; neonatal antiphospholipid syndrome; Cryopyrin-associated periodic syndromes (CAPS); familial cold autoinflammatory syndrome (FCAS); Muckle–Wells syndrome (MWS); neonatal onset multisystem inflammatory disease (NOMID); NLRP3; CIAS 1