SCID and Other Inborn Errors of Immunity with Low TRECs - the Brazilian Experience.

Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of São Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.

Fatores preditores do desfecho do Teste de Provocação Oral na Alergia à Proteína do Leite de Vaca: in natura vs. alimentos processados / Predictors of the outcome of the Oral Food Challenge for Cow's Milk Protein Allergy: raw vs. processed foods

Objetivos: Descrever uma população de crianças com alergia à proteína do leite de vaca (APLV) IgE mediada, submetidas ao teste de provocação oral (TPO) com alimentos processados vs. in natura, e comparar características clínico-epidemiológicas e laboratoriais, avaliando preditores de desfecho ao uso dessas diferentes apresentações de proteína. Métodos: Estudo transversal realizado em ambulatório de alergia de um hospital terciário em Fortaleza, Ceará. A coleta dos dados foi realizada entre outubro de 2018 a setembro de 2019. O questionário foi preenchido com os dados epidemiológicos, clínicos e laboratoriais encontrados no prontuário; amostra total de 49 crianças, com APLV IgE mediada tolerantes ao TPO com alimentos processados ou in natura. Resultados: Na comparação das características clinico-epidemiológicas das populações tolerantes a alimentos in natura vs. processados (respectivamente), a maioria apresentou dados semelhantes, como sexo masculino (60% vs. 57,9%), etnia parda (73,3% vs. 68,4%), idade gestacional a termo (80% vs. 77,8%), sem intercorrências durante a gestação (58,3% vs. 80,0%) ou parto (70% vs. 78,9), média de idade materna (32 anos vs. 35 anos), escolaridade materna (ensino médio completo - 43,3% vs. 47,4%), idade de início dos sintomas de APLV entre 1 e 6 meses (76,7% vs. 68,4%), aleitamento materno exclusivo entre 4 e 6 meses (60% vs. 68,45%), histórico de alergia familiar alimentar (73% vs. 68,4%), sendo as principais comorbidades alérgicas as respiratórias (38,9% vs. 35,7%) e alimentares (38,9% vs. 35,7%). Em relação aos dados laboratoriais, a maioria das frações de proteína no grupo tolerante a alimentos in natura e a alimentos processados apresentou valores ≤ 10 kU/L. Foi constatado que a idade materna (p = 0,006) e a idade de introdução de fórmula complementar (p = 0.020) se correlacionam de forma estatisticamente significante no grupo de pacientes tolerantes a alimentos processados. Conclusões: Foi observado que a idade materna (p = 0,006) e a idade de introdução de fórmula complementar (p=0.020) se correlacionam de forma estatisticamente significante no grupo de pacientes tolerantes alimentos processados. Os dados laboratoriais seguiram distribuição proporcionais entre os dois grupos, com maior frequência de valores ≤ 10 kU/L para todas as frações de proteína do leite de vaca, sem significância estatística. Estudos populacionais semelhantes em populações APLV IgE mediada são importantes para caracterizar melhor esse fenótipo e otimizar ferramentas diagnósticas e protocolos de tratamento. Destaca-se também o papel da terapia baked, que auxilia na aquisição de tolerância a diferentes apresentações da PLV de forma mais breve, melhorando, portanto, a qualidade de vida desses pacientes (AU)

Objectives: To describe the population of children with IgE-mediated CMPA tolerant to processed or raw CMP in the OFC, comparing their clinical, epidemiological and laboratory characteristics and evaluating the possible predictors of outcomes associated with these different presentations of CMP. Methods: Cross-sectional study carried out in an allergy clinic of a tertiary hospital in Fortaleza, Ceará. Data collection was carried out between October 2018 and September 2019. The questionnaire was filled out with epidemiological, clinical and laboratory data found in the medical records. The total sample was composed of 49 children with IgE-mediated CMPA tolerant to processed or raw foods in the OFC. Results: The comparison of the clinical and epidemiological characteristics of populations tolerant to raw foods vs. processed (respectively) showed similarities, such as the predominance of the male gender (60% vs. 57.9%); mixed ethnicity (73.3% vs. 68.4%); delivery at term (80% vs. 77 .8%); no complications during pregnancy (58.3% vs. 80.0%) or childbirth (70% vs. 78.9); mean maternal age (32 years vs. 35 years); level of education of the mothers (complete high school - 43.3% vs. 47.4%); age of onset of CMPA symptoms between 1 and 6 months (76.7% vs. 68.4%); exclusive breastfeeding for 4 to 6 months (60% vs. 68.45%); family history of food allergy (73% vs. 68.4%); and respiratory (38.9% vs. 35.7%) and food allergies (38.9% vs. 35.7%) as the main allergic comorbidities. Regarding laboratory data, most protein fractions had values ≤ 10 kU/L in both groups. It was found that maternal age (p = 0.006) and age of introduction of formula (p = 0.020) were statistically significant in the group of patients tolerant to processed foods. Conclusions: It was observed that maternal age (p = 0.006) and age of introduction of formula (p = 0.020) were statistically significant in the group of patients tolerant to processed foods. Laboratory data were proportionally distributed across the two groups, with a higher frequency of values lower than or equal to 10 kU/L for all CMP fractions, with no statistical significance between the groups. Similar population studies in IgE-mediated CMPA populations are important to better characterize this phenotype and optimize diagnostic tools and treatment protocols. The role of baked therapy is also noteworthy, as it helps patients to develop tolerance to different presentations of CMP more quickly, improving their quality of life (AU)

CD40 Ligand Deficiency in Latin America: Clinical, Immunological, and Genetic Characteristics.

CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

Fatores preditores do desfecho do Teste de Provocação Oral na Alergia à Proteína do Leite de Vaca: in natura vs. alimentos processados / Predictors of the outcome of the Oral Food Challenge for Cow's Milk Protein Allergy: raw vs. processed foods

RESUMO: Objetivos: Descrever uma população de crianças com alergia à proteína do leite de vaca (APLV) IgE mediada, submetidas ao teste de provocação oral (TPO) com alimentos processados vs. in natura, e comparar características clínico-epidemiológicas e laboratoriais, avaliando preditores de desfecho ao uso dessas diferentes apresentações de proteína. Métodos: Estudo transversal realizado em ambulatório de alergia de um hospital terciário em Fortaleza, Ceará. A coleta dos dados foi realizada entre outubro de 2018 a setembro de 2019. O questionário foi preenchido com os dados epidemiológicos, clínicos e laboratoriais encontrados no prontuário; amostra total de 49 crianças, com APLV IgE mediada tolerantes ao TPO com alimentos processados ou in natura. Resultados: Na comparação das características clinico-epidemiológicas das populações tolerantes a alimentos in natura vs. processados (respectivamente), a maioria apresentou dados semelhantes, como sexo masculino (60% vs. 57,9%), etnia parda (73,3% vs. 68,4%), idade gestacional a termo (80% vs. 77,8%), sem intercorrências durante a gestação (58,3% vs. 80,0%) ou parto (70% vs. 78,9), média de idade materna (32 anos vs. 35 anos), escolaridade materna (ensino médio completo - 43,3% vs. 47,4%), idade de início dos sintomas de APLV entre 1 e 6 meses (76,7% vs. 68,4%), aleitamento materno exclusivo entre 4 e 6 meses (60% vs. 68,45%), histórico de alergia familiar alimentar (73% vs. 68,4%), sendo as principais comorbidades alérgicas as respiratórias (38,9% vs. 35,7%) e alimentares (38,9% vs. 35,7%). Em relação aos dados laboratoriais, a maioria das frações de proteína no grupo tolerante a alimentos in natura e a alimentos processados apresentou valores ≤ 10 kU/L. Foi constatado que a idade materna (p = 0,006) e a idade de introdução de fórmula complementar (p = 0.020) se correlacionam de forma estatisticamente significante no grupo de pacientes tolerantes a alimentos processados. Conclusões: Foi observado que a idade materna (p = 0,006) e a idade de introdução de fórmula complementar (p=0.020) se correlacionam de forma estatisticamente significante no grupo de pacientes tolerantes alimentos processados. Os dados laboratoriais seguiram distribuição proporcionais entre os dois grupos, com maior frequência de valores ≤ 10 kU/L para todas as frações de proteína do leite de vaca, sem significância estatística. Estudos populacionais semelhantes em populações APLV IgE mediada são importantes para caracterizar melhor esse fenótipo e otimizar ferramentas diagnósticas e protocolos de tratamento. Destaca-se também o papel da terapia baked, que auxilia na aquisição de tolerância a diferentes apresentações da PLV de forma mais breve, melhorando, portanto, a qualidade de vida desses pacientes. (AU)

ABSTRACS: Objectives: To describe the population of children with IgE-mediated CMPA tolerant to processed or raw CMP in the OFC, comparing their clinical, epidemiological and laboratory characteristics and evaluating the possible predictors of outcomes associated with these different presentations of CMP. Methods: Cross-sectional study carried out in an allergy clinic of a tertiary hospital in Fortaleza, Ceará. Data collection was carried out between October 2018 and September 2019. The questionnaire was filled out with epidemiological, clinical and laboratory data found in the medical records. The total sample was composed of 49 children with IgE-mediated CMPA tolerant to processed or raw foods in the OFC. Results: The comparison of the clinical and epidemiological characteristics of populations tolerant to raw foods vs. processed (respectively) showed similarities, such as the predominance of the male gender (60% vs. 57.9%); mixed ethnicity (73.3% vs. 68.4%); delivery at term (80% vs. 77 .8%); no complications during pregnancy (58.3% vs. 80.0%) or childbirth (70% vs. 78.9); mean maternal age (32 years vs. 35 years); level of education of the mothers (complete high school - 43.3% vs. 47.4%); age of onset of CMPA symptoms between 1 and 6 months (76.7% vs. 68.4%); exclusive breastfeeding for 4 to 6 months (60% vs. 68.45%); family history of food allergy (73% vs. 68.4%); and respiratory (38.9% vs. 35.7%) and food allergies (38.9% vs. 35.7%) as the main allergic comorbidities. Regarding laboratory data, most protein fractions had values ≤ 10 kU/L in both groups. It was found that maternal age (p = 0.006) and age of introduction of formula (p = 0.020) were statistically significant in the group of patients tolerant to processed foods. Conclusions: It was observed that maternal age (p = 0.006) and age of introduction of formula (p = 0.020) were statistically significant in the group of patients tolerant to processed foods. Laboratory data were proportionally distributed across the two groups, with a higher frequency of values lower than or equal to 10 kU/L for all CMP fractions, with no statistical significance between the groups. Similar population studies in IgE-mediated CMPA populations are important to better characterize this phenotype and optimize diagnostic tools and treatment protocols. The role of baked therapy is also noteworthy, as it helps patients to develop tolerance to different presentations of CMP more quickly, improving their quality of life. (AU)

Apresentação atípica de síndrome de hiper-IgM ligada ao X simulando doença inflamatória intestinal / Atypical presentation of X-linked hyper-IgM syndrome simulating inflammatory bowel disease

Relatamos o caso de um paciente do sexo masculino, que iniciou quadro de úlceras em trato gastrointestinal, associado a febre recorrente e diarreia com muco e sangue aos 10 meses de vida, suspeitado inicialmente de doença inflamatória intestinal, no entanto, não apresentou melhora do quadro com terapia imunossupressora, sendo realizada investigação para erro inato da imunidade. Nos exames laboratoriais, apresentou níveis baixos de IgG e IgA e níveis elevados de IgM e neutropenia persistente. Diante disso, foi realizado teste genético que confirmou diagnóstico de síndrome de hiper-IgM ligada ao X. Os erros inatos da imunidade podem se manifestar com doenças do trato gastrointestinal, de forma relativamente frequente, devendo entrar como diagnóstico diferencial de diarreia crônica. Inclusa nesse grupo de doenças, as síndromes de hiper-IgM constituem um grupo heterogêneo de doenças, possuindo em comum níveis significativamente baixos ou ausentes de IgG e IgA e níveis normais ou elevados de IgM, o que predispõe a infecções e febre recorrente; além de outras alterações laboratoriais, como neutropenia, que pode estar associada a úlceras no trato gastrointestinal e proctite, simulando apresentação clínica de doença inflamatória intestinal. Para o paciente relatado, foi iniciada terapia com imunoglobulinas de forma periódica, além de antibioticoprofilaxia para infecções, evoluindo com resposta clínica satisfatória. O artigo possui objetivo principal de alertar para o diagnóstico diferencial de erros inatos da imunidade diante do quadro apresentado, visando o diagnóstico precoce e a instituição da terapia adequada.

We report the case of a male patient, who started with ulcers in the gastrointestinal tract, associated with recurrent fever and diarrhea with mucus and blood at 10 months of life, initially suspected of inflammatory bowel disease, however, he did not improve the condition with immunosuppressive therapy, being investigated for inborn error of immunity. In laboratory tests, he had low levels of IgG and IgA and high levels of IgM and persistent neutropenia. Therefore, a genetic test was performed and confirmed the diagnosis of X-linked hyper IgM syndrome. Inborn errors of immunity can manifest relatively frequently with diseases of the gastrointestinal tract, and should be included as a differential diagnosis of chronic diarrhea. Included in this group of diseases, hyper-IgM syndromes constitute a heterogeneous group of diseases, having in common significantly low or absent levels of IgG and IgA and normal or high levels of IgM, which predispose to infections and recurrent fever; in addition to other laboratory alterations, such as neutropenia, which may be associated with ulcers in the gastrointestinal tract and proctitis, simulating the clinical presentation of inflammatory bowel disease. For the reported patient, therapy with immunoglobulins was started periodically, in addition to antibiotic prophylaxis for infections, evolving with a satisfactory clinical response. The main objective of the article is to alert to the differential diagnosis of inborn errors of immunity in view of the presented condition, aiming at early diagnosis and the institution of adequate therapy.

Outcome of SARS-CoV-2 Infection in 121 Patients with Inborn Errors of Immunity: A Cross-Sectional Study.

PURPOSE: There is still scarce data on SARS-CoV-2 infection in patients with Inborn Errors of Immunity (IEI) and many unresolved questions. We aimed to describe the clinical outcome of SARS-CoV-2 infection in Brazilian IEI patients and identify factors influencing the infection. METHODS: We did a cross-sectional, multicenter study that included patients of any age affected by IEI and SARS-CoV-2 infection. The variables studied were sex, age, type of IEI, comorbidities (number and type), treatment in use for IEI, clinical manifestations and severity of SARS-CoV-2 infection. RESULTS: 121 patients were included: 55.4% female, ages from six months to 74 yo (median age = 25.1 yo). Most patients had predominantly antibody deficiency (n = 53). The infection was mostly asymptomatic (n = 21) and mild (n = 66), and one child had multisystem inflammatory syndrome (MIS-C). We could not observe sex-related susceptibility, and there was a weak correlation between age and severity of infection. The number of comorbidities was higher in severe cases, particularly bronchiectasis and cardiopathy. There were no severe cases in hereditary angioedema patients. Six patients aged 2 to 74 years died, three of them with antibody deficiency. CONCLUSION: The outcome was mild in most patients, but the Case Fatality Ratio was higher than in the general population. However, the type of IEI was not a determining factor for severity, except for complement deficiencies linked to milder COVID-19. The severity of SARS-CoV-2 infection seems to be more related to older age, a higher number of comorbidities and type of comorbidities (bronchiectasis and cardiopathy).

The Challenges in the Follow-Up and Treatment of Brazilian Children with Hereditary Angioedema.

INTRODUCTION: Hereditary angioedema (HAE) with C1 inhibitor (C1-INH) deficiency is a rare autosomal dominant disease. Although the first symptoms can appear in childhood, the diagnosis's delay has a strong impact on the patient's quality of life. We analyzed clinical and laboratory characteristics and the drug therapy of pediatric patients with HAE in Brazil. METHODS: Medical records from 18 reference centers of HAE patients under 18 years of age were evaluated after confirmed diagnosis was performed by quantitative and/or functional C1-INH. RESULTS: A total of 95 participants (51 M:44 F; mean age: 7 years old) out of 17 centers were included; 15 asymptomatic cases were identified through family history and genetic screening. Angioedema attacks affected the extremities (73.5%), gastrointestinal tract (57%), face (50%), lips (42.5%), eyelids (23.7%), genitals (23.7%), upper airways (10%), and tongue (6.3%). Family history was present in 84% of patients, and the mean delay in the diagnosis was 3.9 years. Long-term prophylaxis (51/80) was performed with tranexamic acid (39/80) and androgens (13/80); and short-term prophylaxis (9/80) was performed with tranexamic acid (6/80) and danazol (3/80). On-demand therapy (35/80) was prescribed: icatibant in 7/35, fresh frozen plasma in 16/35, C1-INH plasma-derived in 11/35, and tranexamic acid in 12/35 patients. CONCLUSIONS: This is the first study on HAE pediatric patients in Latin America. Clinical manifestations were similar to adults. Drugs such as androgens and tranexamic acid were indicated off-label, probably due to restricted access to specific drugs. Educational programs should address pediatricians to reduce late diagnosis and tailored child therapy.

CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ.

BACKGROUND: Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. OBJECTIVES: We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function. METHODS: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. RESULTS: Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. CONCLUSION: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.

Polymorphism of IL10, IL4, CTLA4, and DAO Genes in Cross-Reactive Nonsteroidal Anti-inflammatory Drug Hypersensitivity.

Our aim was to evaluate genetic polymorphism of molecules involved in immunoregulatory/allergic processes in patients who presented with cutaneous hypersensitivity caused by chemically unrelated nonsteroidal anti-inflammatory drugs. Polymorphisms at IL10 (-1082 G>A), IL4 (-589 C>T), CTLA4 (+49A>G), and DAO (+8956 C>G) genes were studied in 55 cases and 97 controls by the polymerase chain reaction-restriction fragment length polymorphism technique. With regard to the polymorphism at IL10 -1082, higher frequencies of the AG genotype (57% vs 39%) and G allele carriers (70% vs 48%) were found among the patients, indicating a risk effect (odds ratio [OR] = 2.56 and P = .01 for AG genotype and OR = 2.52; P = .01 for AG/GG). For the CTLA4 +49 A/G single-nucleotide polymorphism (SNP), AG genotype (31.0%) (P = .02) and G carrier (54.0%) (P = .05) frequencies were found to be significantly lower in the patient group compared with the control group (51.0% and 69.0%, respectively). The SNP DAO +8956 C>G was associated with a strong protective effect, with OR values of 0.83 for CG and 0.11 for GG genotype (P = .04 for the codominant model), suggesting an allele dose effect. The combination of IL10 and DAO SNPs in a multivariate model did not alter the OR values, suggesting independent effects for both SNPs. The results are striking. In conclusion, these results suggest that polymorphisms in regulatory targets of the immune response and in DAO gene could modulate an individual's susceptibility to nonsteroidal anti-inflammatory drug hypersensitivity reactions. Further studies will be necessary to complement our results.

Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ.

BACKGROUND: CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated. OBJECTIVES: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses. METHODS: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied. RESULTS: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients. CONCLUSION: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.

First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes.

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Expanding the clinical and genetic spectrum of human CD40L deficiency: the occurrence of paracoccidioidomycosis and other unusual infections in Brazilian patients.

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.

Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis.

BACKGROUND: Patients with X-linked hyper-IgM syndrome (X-HIGM) due to CD40 ligand (CD40L) mutations are susceptible to fungal pathogens; however, the underlying susceptibility mechanisms remain poorly understood. OBJECTIVE: To determine whether monocyte-derived dendritic cells (DCs) from patients with X-HIGM exhibit normal responses to fungal pathogens. METHODS: DCs from patients and controls were evaluated for the expression of costimulatory (CD80 and CD86) and MHC class II molecules and for their ability to produce IL-12 and IL-10 in response to Candida albicans and Paracoccidioides brasiliensis. We also evaluated the ability of C albicans- and P brasiliensis-pulsed mature DCs to induce autologous T-cell proliferation, generation of T helper (T(H)) 17 cells, and production of IFN-γ, TGF-ß, IL-4, IL-5, and IL-17. RESULTS: Immature DCs from patients with X-HIGM showed reduced expression of CD80, CD86, and HLA-DR, which could be reversed by exogenous trimeric soluble CD40L. Most important, mature DCs from patients with X-HIGM differentiated by coculturing DCs with fungi secreted minimal amounts of IL-12 but substantial amounts of IL-10 compared with mature DCs from normal individuals. Coculture of mature DCs from X-HIGM patients with autologous T cells led to low IFN-γ production, whereas IL-4 and IL-5 production was increased. T-cell proliferation and IL-17 secretion were normal. Finally, in vitro incubation with soluble CD40L reversed the decreased IL-12 production and the skewed T(H)2 pattern response. CONCLUSION: Absence of CD40L during monocyte/DC differentiation leads to functional DC abnormalities, which may contribute to the susceptibility to fungal infections in patients with X-HIGM.