A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2)

Abstract Introduction The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. Patients and methods This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. Results Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. Conclusion The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Clinical and Genetic Spectrum of Inborn Errors of Immunity in a Tertiary Care Center in Southern India

Objectives To study the incidence, clinical manifestations, and genetic spectrum of primary immunodefciency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India. Methods A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warranted by the clinical presentation. All families with suspected PID were counseled and ofered genetic testing. Results A total of 225 children were evaluated for PID during the study period of 6 y. Fifty-six of them did not meet the European Society of Immunodefciencies (ESID) criteria (working defnition of clinical diagnosis) and were excluded. An IEI was found in 30/49 (61.2%) patients. The most frequent reason for referral was recurrent/unusual or serious infections (28%), or cytopenia (16%). Group IV diseases of immune dysregulation was the most common category (19%), followed by group III predominant antibody defciencies in 23/163 (14%), as per the International Union of Immunological Societies (IUIS) classifcation. Conclusions This study highlights the heterogeneity of the present cohort, the underuse of genetic tests, and eforts to provide optimal care for children with possible IEI in this center.

Spondyloenchondrodysplasia with immune dysregulation caused by ACP5 gene mutation: a case report and literature review / 中华实用儿科临床杂志

Objective:To summarize the clinical features and gene phenotype of children with spondyloenchondrodysplasia with immune dysregulation (SPENCDI) caused by ACP5 gene mutation. Methods:The medical data and genetic phenotype of a child diagnosed with SPENCDI in the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University in February 23, 2017 were analyzed retrospectively.Besides, " spondyloenchondrodysplasia" were taken as the search terms to perform the retrieval in CNKI, Wanfang Data, and PubMed, in an attempt to conduct the literature review.χ 2 test was used to compare the factors among children with different mutations. Results:The 4.5-year-old girl was admitted to hospital for complaint of " fever and chilblain-like rash" when she was 2 years old.She was diagnosed with systemic lupus erythematosus (SLE) concomitant with lupus nephritis.Methylprednisolone combined with cyclophosphamide, mycophenolate mofetil was used for the treatment.However, she experienced multiple infections, thrombocytopenia, limp, and growth retardation during the treatment.Genetic detection identified ACP5 gene compound hybrid mutation: c.779C>A and c. 770T>C.She was diagnosed with SPENCDI, and was subjected to follow-up.A total of 78 SPENCDI patients were retrieved from the databases, with various clinical manifestations of SPENCDI, commonly with skeletal involvement and immune phenotypes; 73.08% of the cases were positive for antinuclear antibodies, 57.69% of cases were positive for anti-double stranded-DNA antibodies and 34.62% of cases had neurological symptoms.In 58 cases, ACP5 gene mutations were detected, including 44 homozygous mutations and 14 compound heterozygous mutations.Patients with ACP5 gene homozygous mutation had a higher probability of consanguineous marriage in parents [56.82% (25/44 cases) vs.14.29% (2/14 cases)]; patients with ACP5 gene heterozygous mutation were more likely to develop SLE [64.29% (9/14 cases) vs.34.09% (15/44 cases)]( χ2=7.722, 3.992; all P<0.05). Conclusions:The majority of the ACP5 gene mutations are homozygous mutations in patients with SPENCDI, and heterozygous mutations are rare.The clinical manifestations of SPENCDI are various and complex, it is prone to develop autoimmune diseases, and there was no clear correlation between clinical features and gene phenotype in SPENCDI patients.

The effect of ribophagy on lipopolysaccharide-induced apoptosis of dendritic cells / 中华急诊医学杂志

Objective:To investigate the role and significance of NUFIP-1-mediated ribophagy in apoptosis of dendritic cells (DCs) stimulated by lipopolysaccharide (LPS).Methods:Cultured mouse dendritic cell line DC2.4 were divided into the blank control group and LPS stimulation groups for 6, 12, 24, 48 and 72 h ( n=5). LPS subgroups were consistently cultured with 1 μg/mL LPS for the corresponding incubation time. Western blot was adopted to detect the expression levels of NUFIP-1 and autophagy-related proteins p62 and LC3B across groups. Laser scanning confocal microscopy (LSCM) was applied to detect the expression and cellular localization of NUFIP-1, with its co-localization with Lyso-tracker and LC3B, respectively. The silencing blank vector NS and silencing virus vector NUFIP-1 siRNA were transferred into DC2.4 ( n=3) and stimulated with 1 μg/mL LPS for 24 h. The apoptosis of DC2.4 was measured by flow cytometry analysis. The expression levels of apoptosis-related proteins were determined using Western blot, including cleaved caspase-3 and Bcl-2. One-way analysis of variance (ANOVA) was applied for comparison among multiple groups, and LSD-t method was used for subsequent pairwise comparison. A P<0.05 was considered statistically significant. Results:The results of Western blot showed that expression level of NUFIP-1 in DC2.4 revealed a trend of first increasing and subsequent decreasing upon LPS stimulation for different times (6, 12, 24, 48 and 72 h), and the expression level of NUFIP-1 in the LPS 24 h group was significantly higher than that in the blank control group [blank control group: (0.6786 ± 0.0820); LPS 24 h group: (1.4830 ± 0.1170); P<0.01]. Meanwhile, p62 expression in the LPS 24 h group was significantly lower than that in the blank control group [blank control group: (0.9087 ± 0.1235); LPS 24 h group: (0.3113 ± 0.5571); P<0.01]. Moreover, the conversion from LC3B-I to LC3B-II in the LPS 24 h group was significantly higher than that in the blank control group [blank control group: (0.5542 ± 0.1248); LPS 24 h group: (2.5310 ± 0.3119); P<0.01]. LSCM indicated that NUFIP-1 was predominantly located in the nucleus and perinuclear area in DC2.4. The fluorescence intensity of NUFIP-1 increased in a time-dependent manner from 6 h to 24 h after LPS stimulation, whereas a significant reduction could be observed at 48 h and 72 h after LPS stimulation. Meanwhile, the co-localization of NUFIP-1 with Lyso-tracker and LC3B was substantially reinforced in comparison with the blank control group. Transfection of NUFIP-1 siRNA through lentivirus transfection technology significantly down-regulated the expression level of NUFIP-1 in DC2.4, with statistical differences compared with the blank control group and empty vector group [blank control group: (0.6627 ± 0.1707); empty vector group: (0.6966 ± 0.1107); siRNA group: (0.1428 ± 0.0296); P<0.05]. Flow cytometry analysis revealed that the apoptotic rate of LPS-stimulated DC2.4 was significantly higher in the NUFIP-1 siRNA transfection group than that in the blank control group and empty vector group [blank control LPS 24 h group: (47.91% ± 1.006%); empty vector LPS 24 h group: (70.26% ± 1.011%); siRNA LPS 24 h group: (80.23% ± 2.094); P<0.01]. Western blot analysis of apoptosis-related protein further confirmed that the expression level of cleaved caspase-3 was significantly elevated in the NUFIP-1 siRNA transfection group compared to those of the blank control group and empty vector group under LPS challenge [blank control LPS 24 h group: (0.4748 ± 0.0876); empty vector LPS 24 h group: (0.2849 ± 0.0418); siRNA LPS 24 h group: (0.9733 ± 0.0525); P<0.01]. Likewise, expression of Bcl-2, an anti-apoptotic protein was significantly down-regulated in the siRNA LPS 24 h group [blank control LPS 24 h group: (0.7810 ± 0.0490); empty vector LPS 24 h group: (0.8292 ± 0.0729); siRNA LPS 24 h group: (0.3957 ± 0.0838); P<0.05]. Conclusions:NUFIP-1-mediated ribophagy is significantly activated in DC2.4 upon LPS stimulation, exerting an underlying protective effect on apoptosis.

Progress of physiological dysfunctions in autism spectrum disorder / 国际儿科学杂志

Autism spectrum disorder(ASD)is a group of highly heterogeneous neurodevelopmental disorders with different kinds of physiological dysfunctions.Based on the literature reports, physiological dysfunctions of ASD mainly focus on four aspects, including immune dysregulation/ inflammation, oxidative stress, mitochondrial dysfunction and environmental toxin exposure.This review focuses on the main manifestations of the four physiological abnormalities in patients with ASD, aiming to illustrate the relationship between various physiological abnormalities and autism, providing clues for the research, treatment and prevention strategies of ASD.

Analysis of components of proteins from Echinococcus granulosus cyst fluid / 中国血吸虫病防治杂志

Objective To analyze the components of proteins from Echinococcus granulosus cyst fluid using the shotgun method, and to identify the active components with potential regulatory effects for immune dysregulation diseases. Methods The E. granulosus cyst fluid was collected aseptically from the hepatic cysts of patients with cystic echinococcosis, and characterized by liquid chromatography (LC) tandem mass spectrometry (MS/MS) following digestion with trypsin. The protein data were searched using the software MaxQuant version 1.6.1.0 and the cellular components, molecular functions, and biological processes of the identified proteins were analyzed using the Gene Ontology (GO) method. Results The E. granulosus cyst fluid separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) had a relative molecular mass of 25 to 70 kDa. LS-MS/MS analysis identified 37 proteins, including 32 known proteins and 5 unknown proteins. At least 4 proteins were preliminarily found to exhibit potential regulatory effects for immune dysregulation diseases, including antigen B, glutathione-S-transferase (GST), thioredoxin peroxidase (TPX) and malate dehydrogenase (MDH). GO enrichment analysis showed that the identified proteins had 149 molecular functions and were involved in 341 biological processes. Conclusions E. granulosus cyst fluid has a variety of protein components, and four known proteins are preliminarily identified to be associated with immune dysregulation diseases.

Role of the ES-62 protein derived from Acanthocheilonema viteae in regulation of immune dysregulation diseases: a review / 中国血吸虫病防治杂志

ES-62 is a phosphorylcholine-containing, 62 kDa glycoprotein derived from the excretory-secretory product of Acanthocheilonema viteae, which is effective for the prevention and treatment of immune dysregulation diseases through triggering activation of immune cells, such as dendritic cells, mononuclear macrophages and regulatory B cells and mediating immune responses. Recently, the role of the ES-62 protein in the management of allergic, autoimmune and metabolic diseases has been paid much attention. This review summarizes the regulatory role of the ES-62 protein in immune dysregulation diseases and the underlying mechanisms, so as to provide insights into future experimental studies.

Índice de desregulación inmunológica como predictor de evolución hacia síndrome de insuficiencia respiratoria progresiva del adulto en pacientes con neumonía por SARS-CoV-2 / Immune dysregulation index as a predictor of evolution to acute respiratory distress syndrome in patients with SARS-CoV-2 pneumonia / Índice de disregulação imunológica como preditor da evolução da síndrome de insuficiência respiratória progressiva do adultos em pacientes com pneumonia por SARS-CoV-2

Resumen: Introducción: Se han descrito los principios fisiopatológicos de la neumonía secundaria a infección por SARS-CoV-2, en donde se identificó la cascada de citocinas como principal factor para el desarrollo de lesiones orgánicas. Actualmente, se realizan mediciones de marcadores bioquímicos inflamatorios en la búsqueda de su relación con el pronóstico y posibles complicaciones. En un estudio reciente, se realizó un índice relacionando la interleucina 6 y los niveles de linfocitos y su asociación con la mortalidad en los pacientes con neumonía severa por SARS-CoV-2. El índice de desregulación inmunológica (IL-6/linfocitos) podría permitir estimar a los pacientes que evolucionarán hacia síndrome de insuficiencia respiratoria progresiva del adulto (SIRPA). Objetivos: Establecer si existe una relación entre el nivel de índice de desregulación inmunológica y la aparición del síndrome de insuficiencia respiratoria progresiva del adulto, en los pacientes con neumonía por SARS-CoV-2. Material y métodos: Se realizó el estudio observacional y retrolectivo de una cohorte, en el cual se incluyeron pacientes internados en el Centro Médico ABC con el diagnóstico de neumonía por SARS-CoV-2 de marzo a julio del año 2020, en quienes se realizaron mediciones de interleucina 6 y linfocitos de ingreso, se evaluó su progreso y desarrollo de complicaciones. Se efectuó un análisis univariado de los factores seleccionados, el procesamiento estadístico se elaboró en SPSS v 22.1, se determinaron medidas de frecuencia y de los factores de riesgo con pruebas de Fisher y χ2. Resultados: Se analizaron 346 pacientes, el índice de desregulación inmunológica presentó un promedio de 157 en el grupo correspondiente a SIRPA, mientras que en el grupo control el promedio fue de 38. De los pacientes con diagnóstico de SIRPA, el 18.6% fallecieron, mientras que dentro del grupo control sólo 0.47%. La curva ROC para el análisis de la sensibilidad y especificidad del índice como predictor de evolución hacia SIRPA resultó con un hallazgo de sensibilidad de 68.2% y una especificidad de 77% con un punto de corte de 99. Conclusión: La predicción de complicaciones en el contexto de SARS-CoV-2 permitirá tomar medidas oportunas; por lo que la existencia de índices predictivos es una herramienta útil pero que requiere análisis múltiples y validados en distintas poblaciones para contar con un nivel de seguridad alto al tomar decisiones basadas en ellos.En este estudio en particular, el índice de desregulación inmunológica se ha mostrado como un posible predictor de evolución hacia SIRPA; sin embargo, el establecimiento de medidas terapéuticas deberá continuar con relación a hallazgos clínicos, bioquímicos y de imagen.

Abstract: Introduction: The pathophysiological principles of pneumonia secondary to SARS-CoV-2 infection have been described, where the cytokine cascade was identified as the main factor for the development of organic lesions. Measurements of inflammatory biochemical markers are currently being carried out in search of their relationship with prognosis and possible complications. In a recent study, an index was made relating interleukin 6 and lymphocyte levels and their association with mortality in patients with severe SARS-CoV-2 pneumonia. The index of immune dysregulation (IL-6/lymphocytes) could allow estimating the patients that evolve towards acute respiratory distress syndrome. Objectives: To establish whether there is a relationship between the levels of the immune dysregulation index and the appearance of acute respiratory distress syndrome in patients with SARS-CoV-2 pneumonia. Material and methods: We conducted a retrolective, observational cohort study, in which patients admitted to the ABC Medical Center with the diagnosis of pneumonia due to SARS-CoV-2 from March to July of 2020 were included, in them, measurements of interleukin 6 and lymphocytes on admission and their progress and development of complications were evaluated. A univariate analysis of the selected factors was carried out; the statistical analysis was elaborated in SPSS v 22.1, frequency measures were examined and the analysis of the risk factors was carried out with the Fisher and χ2 tests. Results: 346 patients were analyzed, the immune dysregulation index presented an average of 157 in the group corresponding to ARDS, while in the control group the average was 38. Of the patients with a diagnosis of ARDS, 18.6% died, while in the control group only 0.47%. The ROC curve was used for the analysis of the sensitivity and specificity of the index as a predictor of evolution towards ARDS with a sensitivity finding of 68.2% and a specificity of 77% with a cut-off point of 99. Conclusion: The prediction of complications in the context of SARS-CoV-2 will allow timely measures to be taken. The existence of predictive indices is a useful tool but it requires multiple and validated analyses in different populations to have a high level of safety when making decisions based on them. In this study, the immune dysregulation index has been shown as a possible predictor of evolution towards ARDS; however, the establishment of therapeutic measures should continue in relation to clinical, biochemical and imaging findings.

Resumo: Introdução: São descritos os princípios fisiopatológicos da pneumonia secundária à infecção por SARS-CoV-2, onde a cascata de citocinas foi identificada como o principal fator para o desenvolvimento de lesões orgânicas. Medidas de marcadores bioquímicos inflamatórios estão sendo realizadas em busca de sua relação com o prognóstico e possíveis complicações. Em um estudo recente, foi realizado um índice relacionando os níveis de interleucina 6 e de linfócitos e sua associação com a mortalidade em pacientes com pneumonia por SARS-CoV-2 grave. O índice de desregulação imunológica (IL-6/linfócitos) poderia permitir estimar os pacientes que irão evoluir para a síndrome do desconforto respiratório progressivo em adultos (SIRPA). Objetivos: Estabelecer se há uma relação entre o nível do índice de desregulação imunológica e o aparecimento da síndrome de insuficiência respiratória progressiva do adulto em pacientes com pneumonia por SARS-CoV-2. Material e métodos: Foi realizado um estudo de coorte observacional, retroletivo, que incluiu pacientes internados no Centro Médico do ABC com diagnóstico de pneumonia por SARS-CoV-2 de março a julho deste ano, nos quais foram realizadas dosagens de interleucina 6 e linfócitos na admissão, sua evolução e desenvolvimento de complicações. Realizou-se a análise univariada dos fatores selecionados, a análise estatística foi elaborada no SPSS v 22.1, as medidas de frequência e os fatores de risco foram determinados com teste de Fisher e χ2. Resultados: Foram analisados 346 pacientes, o índice de desregulação imunológica apresentou média de 157 no grupo correspondente ao SIRPA, enquanto no grupo controle a média foi de 38. Dos pacientes com diagnóstico de SIRPA 18.6% morreram durante o grupo controle apenas 0.47%. A curva ROC para análise da sensibilidade e especificidade do índice como preditor de evolução para SIRPA com uma de sensibilidade de 68.2% e uma especificidade de 77% com um ponto de corte de 99. Conclusão: A previsão de complicações no contexto da SARS-CoV-2 nos permitirá tomar medidas oportunas; portanto, a existência de índices preditivos é uma ferramenta útil, mas requer análises múltiplas e validadas em diferentes populações para ter um alto nível de segurança ao tomar decisões com base neles. Neste estudo em particular, o índice de desregulação imunológica foi mostrado como um possível preditor de evolução para SIRPA; entretanto, o estabelecimento de medidas terapêuticas deve continuar em relação aos achados clínicos, bioquímicos e de imagem.

Two case reports about immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and literature review / 中国小儿急救医学

Objective To explore the clinical manifestation,laboratory findings,treatment and prog-nosis of immune dysregulation,polyendocrinopathy,enteropathy,X-linked ( IPEX) syndrome,and to improve pediatricians'knowledge of this disease. Methods Clinical data of two cases of IPEX were retrospectively analyzed,and related literatures were reviewed. Results One of the two male children showed severe and early-onset enteropathy,another showed insulin-dependent diabetes onset. Both of them complicated with sep-sis. DNA sequencing of whole-genome exon group showed a mutation in FOXP3 gene. Finally,one of the two IPEX children accepted allogeneic hematopoietic stem cell transplantation( HSCT) . Another one was waiting for the treatment of HSCT. Conclusion IPEX should be considered also in infants with typical symptoms including early-onset refractory diarrhea, multiple endocrine disease and severe recurring infections. Gene sequencing mayl help diagnose the disease. Early HSCT can improve the patients'outcomes.

IPEX with congenital ichthyosiform skin lesions:a case report and literature review / 临床儿科杂志

Objective To explore the clinical phenotype, treatment and prognosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and to improve pediatricians' knowledge of this disease. Methods Clinical data of a case of IPEX with congenital ichthyosiform skin lesions were retrospectively analyzed, and related literatures China were reviewed. Results The 2-month-11-day old boy came to our hospital due to ichthyosiform skin lesions accompanied by blood oozing in the head and feet exudatation, with severe sepsis and gastrointestinal perforation. He was died of multiple organ failure. DNA sequencing of whole-genome exon group showed a hemizygous mutation of c.1150G> A, p.A384> T in FOXP3 gene. His mother was a heterozygous mutation carrier, while his father was normal. Conclusions In addition to typical symptoms including early-onset refractory diarrhea, multiple endocrine disease and growth retardation, IPEX should be considered also in infants with ichthyosiform rash and severe infection. Gene sequencing will help diagnose the disease.

Genetic diagnosis of spondyloenchondrodysplasia with immune dysregulation:a case report and literature review / 临床儿科杂志

Objective To investigate the clinical and laboratory diagnosis in a rare case with dwarifsm and multisystem abnormalities. Methods Whole-exome sequencing was performed and data was processed using high-throughput data analysis pipeline. Genetic test result is veriifed by Sanger sequencing. Results This is a 14-year-old boy with short stature (the height is 132 cm) and autoimmune hemolytic anemia. He was treated with long-term oral prednisone. Head CT from other hospital found multiple calciifcations on both sides of the basal ganglia, two sides of the frontal lobe, and the left side of parietal lobe. Lateral spinal X-ray photography showed lfat in thoracolumbar vertebral body. Valgus was surgically corrected. He also has facial pigmentation spot and onychomycosis. Whole-exome sequencing combined with Sanger sequencing identiifed a known homozygous pathogenic mutation in ACP 5 genes (c. 643 G>A, p.G 215 R). Identiifcation of such a mutation results in the diagnosis of spondylo enchondrody splasia with immune dysregulation (SPENCDI). Conclusions Whole-exome sequencing is one of the effective methods for detection of rare disease, the SPENCDI case reported here is a good example of it.

Reference Values for a Panel of Cytokinergic and Regulatory Lymphocyte Subpopulations

Lymphocyte subpopulations producing cytokines and exerting regulatory functions represent key immune elements. Given their reciprocal interdependency lymphocyte subpopulations are usually assayed as diagnostic panels, rather than single biomarkers for specialist clinical use. This retrospective analysis on lymphocyte subpopulations, analyzed over the last few years in an outpatient laboratory in Northeast Italy, contributes to the establishment of reference values for several regulatory lymphocytes currently lacking such reference ranges for the general population. Mean values and ranges in a sample of Caucasian patients (mean age 42±8,5 years), were provided for Th1, Th2, Th17, Th-reg, Tc-reg, Tc-CD57⁺ and B1 lymphocytes. The results are consistent with what is found in literature for the single subtypes and are: Th1 157.8±60.3/µl (7.3%±2.9); Th2 118.2±52.2/µl (5.4%±2.5); Th17 221.6±90.2/µl (10.5%±4.4); Th-reg 15.1±10.2/µl (0.7%±0.4); Tc-reg 5.8±4.7/µl (0.3%±0.2); Tc-CD57+ 103.7±114.1/µl (4.6%±4.7); B1 33.7±22.8/µl (1.5%±0.9); (Values are mean±SD). The results show that despite their variability, mean values are rather consistent in all age or sex groups and can be used as laboratory internal reference for this regulatory panel. Adding regulatory cells to lymphocyte subpopulations panels allows a more complete view of the state of the subject's immune network balance, thus improving the personalization and the “actionability” of diagnostic data in a systems medicine perspective.

Advances of immunologic dysregulation mechanism in biliary atresia / 中华实用儿科临床杂志

Biliary atresia(BA) is a destructive inflammatory obliterative cholangiopathy of neonates affecting both intrahepatic and extrahepatic bile ducts.BA is more common in east Asia.Genetic susceptibility,viral infections,and immune dysregulation may be related to BA,but immune dysregulation may play a key hole in the pathogenesis of BA.A current view of the pathogenesis of BA is that it may involve both a primary perinatal hepatobiliary viral infection and a secondary generation of an autoimmune-mediated bile duct epithelial injury.The etiology of BA is unknown,but there is evidence for the involvement of immunologic dysregulation mechanisms,which will be discussed in this review.

Diagnostic Approach to Primary Immunodeficiency Disorders.

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of inherited disorders that affect different components of the immune system. There are more than 150 different disorders which have been described till date. Despite major advances in the molecular characterization of PIDs over the last 20 years, many patients remain undiagnosed or are diagnosed too late with severe consequences. Recognizing different clinical manifestations of PID is the first most important step. It should be followed by use of appropriate diagnostic tools from a vast number of investigations available. This review will focus on important presenting features of PID and laboratory approach for diagnosis of suspected cases of PID.

Schizophrenia and Immunological Abnormalities

There have been vast amount studies regarding immunologic dysregulation in schizophrenia. The mechanism of immune pathogenesis in schizophrenia still is unclear, even though various immune dysfunction have been reported. We endeavored to report on two major hypothesis on immunologic dysregulation in schizophrenia, the infection hypothesis and autoimmune hypothesis. We went on to focus on the autoimmune hypothesis, which has received the most attention over the years. We explored the accumulated data and the rational behind the autoimmune hypothesis and the implications of the autoimmune hypothesis for future research in the pathogenesis of schizophrenia