Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil.

Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott-Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4(+) lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE.

Associação de imunodeficiência primária com lúpus eritematoso sistêmico: revisão da literatura e as lições aprendidas pela Divisão de Reumatologia de um hospital universitário terciário em São Paulo / Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil

Resumo As imunodeficiências primárias (IDP) representam um grupo heterogêneo de doenças resultantes de defeitos hereditários no desenvolvimento, na maturação e na função normal de células do sistema imunológico; assim, tornam os indivíduos suscetíveis a infecções recorrentes, alergia, autoimunidade e doenças malignas. Neste estudo retrospectivo descrevem-se doenças autoimunes (DAI), em especial o lúpus eritematoso sistêmico (LES), que surgiram associadas ao curso das IDP. Classicamente, a literatura descreve três grupos de IDP associadas ao LES: (1) deficiência de componentes da via do complemento, (2) defeitos na síntese de imunoglobulinas e (3) doença granulomatosa crônica (DGC). Na atualidade, outras IDP têm sido descritas como manifestações clínicas do LES, como a síndrome de Wiskott-Aldrich (WAS), a poliendocrinopatia autoimune-candidíase-distrofia ectodérmica (APECED), a síndrome linfoproliferativa autoimune (ALPS) e a linfocitopenia idiopática CD4+. Também são apresentados achados de uma coorte de adultos do ambulatório da Divisão de Reumatologia da Universidade Federal de São Paulo. As manifestações de IDP encontradas pelo nosso grupo de estudo foram consideradas leves em termos de gravidade de infecções e mortalidade no início da vida. Assim, é possível que alguns estados de imunodeficiência sejam compatíveis com a sobrevivência em relação à suscetibilidade infecciosa; no entanto, esses estados podem representar um fator de predisposição forte para o desenvolvimento de doenças imunológicas, como observado no LES.

Abstract Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott–Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4+ lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE.

Imunodeficiência combinada grave: uma revisão da literatura / Severe combined immunodeficiency: review of the literature

A imunodeficiência combinada grave (SCID) é uma condição clínica caracterizada por marcante comprometimento da resposta imune envolvendo linfócitos T e/ou B e/ou células NK, que conduza aumento da susceptibilidade a infecções e alta taxa de mortalidade em crianças acometidas. Dificuldades na interpretação dos sintomas clínicos e na identificação de mutações genéticas, devido à ampla variedade fenotípica e genotípica da doença, representam obstáculos para o diagnóstico. Por outro lado, o tratamento é realizado de forma independente da identificação de mutação genética. O objetivo do presente trabalho foi revisar aspectos fisiopatológicos, métodos diagnósticos e tratamentos utilizados em pacientes com SCID. A revisão foi realizada com base em levantamento bibliográfico de banco de dados indexados disponíveis na Internet incluindo LILACS, MEDLINE, PubMed, SciELO Brasil, periódicos CAPES e Cochrane, e foi conduzida com os seguintes critérios de inclusão: artigos científicos publicados nos idiomas português e inglês, dentro do período de 1963 a 2014 e que possuíam as palavras-chave “Imunodeficiência Combinada Grave”, “SCID”, “Leucopenia”, “Diagnóstico”, “Tratamento” e “Transplante de medula óssea”. O levantamento bibliográfico revelou dificuldades no diagnóstico clínico, laboratorial e genético-molecular, e ressaltou a importância do diagnóstico precoce conduzindo ao tratamento adequado. O diagnóstico precoce da SCID tem papel crucial na melhora da qualidade de vida e na sobrevida dos pacientes, além de favorecer intervenções terapêuticas que previnem o surgimento de infecções e complicações clínicas subsequentes...

Severe combined immunodeficiency (SCID) is a clinical condition characterized by marked impairment of immune responses involving T and/or B lymphocytes and/or NK cells, leading to increased susceptibility to infections and a high mortality rate among affected infants. Difficulties in the interpretation of clinical symptoms and in the detection of genetic mutations make diagnosis a challenge because of the phenotypic and genotypic heterogeneity associated with the disease. Treatment is performed regardless of the detection of a genetic mutation. The objective of the present study was to review pathophysiological aspects, diagnostic methods, and therapies used in patients with SCID. The review included papers available in online databases, including LILACS, MEDLINE, PubMed, SciELO Brazil, Periódicos CAPES, and Cochrane. Papers were searched considering the following inclusion criteria: research articles published in Portuguese or English, between years 1963 and 2014, containing the keywords "Severe Combined Immunodeficiency," "SCID," "Leukopenia," "Diagnosis," "Treatment," and "Bone Marrow Transplantation." The review revealed difficulties in clinical, biochemical, and molecular genetic diagnosis, and emphasized the importance of early diagnosis leading to appropriate treatment. Early diagnosis of SCID is crucial to improve the quality of life and survival of patients, and it allows the use of therapeutic interventions that prevent the onset of infections and subsequent clinical complications...

Toll-like receptors' pathway disturbances are associated with increased susceptibility to infections in humans.

Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity. Currently, 11 members of TLRs have been identified in humans, with important function in host defense in early steps of the inflammatory response. TLRs are present in the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6) and endosome (TLR3, TLR7, TLR8, TLR9) of leukocytes. TLRs and IL-1R are a family of receptors related to the innate immune response that contain an intracellular domain known as the Toll-IL-1R (TIR) domain that recruits the TIR-containing cytosolic adapters MyD88, TRIF, TIRAP and TRAM. The classical pathway results in the activation of both nuclear factor κB and MAPKs via the IRAK complex, with two active kinases (IRAK-1 and IRAK-4) and two non-catalytic subunits (IRAK-2 and IRAK-3/M). The classical pro-inflammatory TLR signaling pathway leads to the synthesis of inflammatory cytokines and chemokines, such as IL-1ß, IL-6, IL-8, IL-12 and TNF-α. In humans, genetic defects have been identified that impair signaling of the TLR pathway and this may result in recurrent pyogenic infections, as well as virus and fungi infections. In this review, we discuss the main mechanisms of microbial recognition and the defects involving TLRs.

HOX antisense lincRNA HOXA-AS2 is an apoptosis repressor in all trans retinoic acid treated NB4 promyelocytic leukemia cells.

HOXA cluster antisense RNA 2 (HOXA-AS2) is a long non-coding RNA located between the HOXA3 and HOXA4 genes in the HOXA cluster. Its transcript is expressed in NB4 promyelocytic leukemia cells and human peripheral blood neutrophils, and expression is increased in NB4 cells treated with all trans retinoic acid (ATRA). Knockdown of HOXA-AS2 expression by transduced shRNA decreases the number of viable cells and increases the proportion of apoptotic cells, measured by annexin V binding and by activity and cleavage of caspases-3, -8, and -9. The increase in death of HOXA-AS2 knockdown cells was accompanied by an elevated TNF-related apoptosis-inducing ligand (TRAIL) levels, but ATRA-induced NB4 cells treated with TRAIL did show an increase in HOXA-AS2 expression. These results demonstrate that ATRA induction of HOXA-AS2 suppresses ATRA-induced apoptosis, possibly through a TRAIL-mediated pathway. HOXA-AS2-mediated negative regulation thus contributes to the fine-tuning of apoptosis during ATRA-induced myeloid differentiation in NB4 cells.

Neutropenia congênita / Congenital neutropenia

Buscamos aqui revisar os mecanismos imunopatológicos relacionados à neutropenia congênita.O termo neutropenia congênita é utilizado para designar uma série de distúrbios neutropênicos,de caráter permanente, intermitente, grave (< 500 neutrófilos/mm3 de sangue), ou moderado(entre 500-1.500 neutrófilos/mm3 de sangue), que podem acometer pele e mucosa do tratorespiratório e gastrintestinal. Quando a neutropenia é diagnosticada, ela deve ser distinguidadas formas adquiridas, incluindo a neutropenia pós-viral e a autoimune, da forma congênita,que pode ser uma enfermidade isolada ou fazer parte de uma doença genética. Cinquenta porcento das formas congênitas de neutropenia apresentam manifestação extra-hematopoiéticacom resposta imune adaptativa normal e infecções recorrentes no início da vida. O tratamentodestes pacientes tem por objetivo o controle e a prevenção de infecções através do uso profiláticode antibióticos, e outra forma de tratamento consiste na utilização de fator estimuladorde colônia de granulócitos recombinante humano (rHUG-CSF), que aumenta o número degranulócitos, diminui o número infecções e melhora de forma significativa a sobrevida e qualidadede vida. A revisão foi realizada por levantamento bibliográfico de banco de dados obtidosatravés de pesquisa direta, LILACS, MEDLINE e capítulos de livros. A revisão literária demonstraa importância dos neutrófilos pela defesa do hospedeiro contra micro-organismos, e defeitosgenéticos que envolvem estas células acarretam maior susceptibilidade a infecções microbianasem locais como pele e mucosa do trato respiratório e gastrintestinal. Estes defeitos genéticosdos neutrófilos envolvem o seu número, função, ou ambos. Como estes defeitos envolvendofagócitos são de caráter congênito e hereditário, as crianças são os pacientes predominantes. Osneutrófilos apresentam um papel importante na imunidade inata, prevenindo o surgimento deinfecções de repetição. O tratamento com rHUG-CSF aumenta o número de granulócitos, diminuio número de novas infecções e melhora de forma significativa a sobrevida e qualidade de vida.O transplante de células-tronco hematopoiéticas é indicado em casos refratários ao tratamentocom rHUG-CSF que apresentam infecções recorrentes graves e resistência ao tratamento semdetecção de mielodisplasia/leucemia.

Here we aim to review pathogenic mechanisms related to congenital neutropenia. The termcongenital neutropenia has been used to designate a series of neutropenic disorders that canbe permanent, intermittent, severe (< 500 neutrophils/mm3) or moderate (500-1500 neutrophils/mm3), which could affect the skin and mucosa of the respiratory and gastrointestinal tracts. Whenneutropenia is diagnosed, it is necessary to distinguish between the acquired form, includingpost-viral and autoimmune neutropenia, and the congenital form, a disease that can occur eitheralone or as part of a genetic disease. Fifty percent of the congenital forms of neutropenia haveextra-hematopoietic manifestations, with normal adaptive immune response and recurrent infections in early life. Treatment of these patients focuses primarily on controlling and preventing infections through the use of prophylactic antibiotics; another treatment approach is the use of recombinant human granulocyte colony-stimulating factor (rHUG-CSF), which increases the number of granulocytes, reduces the number of infections, and significantly improves survival rates and quality of life in these patients. Papers were directly searched on the LILACS and MEDLINE database Book chapters were also reviewed. The literature reviewed underscores theimportance of neutrophils for host defense against microorganisms and the association betweengenetic defects involving these cells and an increased susceptibility to microbial infections inthe skin and mucosa of the respiratory and gastrointestinal tracts. Genetic defects may affectneutrophil number, function, or both. Because defects involving phagocytes have a congenitaland hereditary origin, children are the most common patients. Neutrophils have an importantrole in innate immunity, preventing the emergence of recurrent infections. Treatment withrHUG-CSF increases the number of granulocytes, decreases the number of new infections, andsignificantly improves survival rates and quality of life. Hematopoietic stem cell transplantationis indicated in patients refractory to rHUG-CSF treatment with severe and recurrent infectionsand resistance to treatment with no detection of myelodysplasia/leukemia.