Academic literature on the topic 'Immunodeficienza comune variabile'

ABSTRACT The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection.

Abstract T-bodies that combine the antigen recognition capability of single chain antibody molecules (scFv) with the signal transduction domains of activating receptors can be used to generate T cells with novel, engineered specificities independent of their endogenous TCR. We have developed a series of T-bodies with specificity towards CD19, a molecule with expression that appears restricted to normal and malignant B cells. These T-bodies contain the activating signals from the costimulatory T cell receptors, CD28 and/or 4-1BB, in tandem with the TCR-ζ signal transduction domain. Using lentiviral gene transfer and T cells expansion via bead-immobilized anti-CD3 and anti-CD28 antibodies, we can generate T cells 95% of which express the T-bodies. Lentiviral transduction combined with this efficient T cell expansion system has the potential to produce >1011 antigen-specific T cells without the need for a cell selection step. Interestingly, we have noted significant constitutive signaling effects of T-body overexpression on transduced T cells that may been overlooked previously due to lower transduction efficiency. Despite the observed constitutive effects, we show that lentiviral-engineered T cells expressing anti-CD19 T bodies efficiently kill CD19 expressing cell lines and primary B-ALL cells in an antigen-specific manner. T-body engineered T cells also produce cytokines in response to antigen triggering with different patterns of cytokine production by T cells engineered with different T-bodies. In particular, a T-body receptor containing the 4-1BB signal transduction domain combined with the TCR-ζ domain stimulates a >6-fold increase in IL-6 production compared with other receptor combinations in CD4+ T cells. In contrast, a CD28 and TCR-ζ domain containing T body uniquely enhances IL-2 (>3-fold) and TNF-α (> 7-fold) secretion by CD8+ T cells. These results indicate that the functional characteristics of our tested T-body signaling constructs are distinct and depend upon the particular receptor and T cell subset combination. We are also comparing the anti-tumor response generated by adoptively transferred T-body engineered T cells in leukemia bearing immunodeficient mice as a pre-clinical, therapeutic model. In addition to elucidating important functional differences of our lentiviral constructs, these studies indicate that an important variable in clinical trials will be optimizing the cytosolic signaling domain for the desired T cell subset. The present results suggest that distinct combinatorial signaling domains may be required for optimal function in CD4 and CD8 engineered T cells.

Abstract Abstract 574 Relapsed and refractory pediatric acute lymphocytic leukemia (ALL) remains a difficult therapeutic challenge and accounts for a sizable number of cancer-related deaths in children. Chimeric antigen receptors (CAR) are genetically engineered molecules that combine antibody specificity for a target antigen with the potent cytotoxic potential of activated T cells. CAR based T cell immunotherapy is currently under study in several clinical trials and encouraging early response data is beginning to emerge. However, studies in pediatric malignancies are still lacking. We have studied the efficacy of a second-generation CAR containing the T-cell receptor zeta signaling subunit, the signaling domain of CD28, and a single chain variable fragment directed against CD19. CD19 is present on nearly 100% of pediatric ALL blasts and normal B cells but not on hematopoietic stem cells. Anti-CD19-CAR T cells are generated using retroviral transduction of T cells activated with K562 based artificial antigen presenting cells expressing the high-affinity Fc-receptor (CD64) loaded with anti-CD3 and the co-stimulatory molecule, 41BB-ligand. Transduction efficiency, as measured by flow cytometry, averaged 50–80%. Unselected anti-CD19-CAR T-cells specifically and robustly killed four CD19+ ALL but not CD19– target cell lines (45-60% lysis at E:T ratios as low as 2.5:1 in 4h 51Cr release assay) and produced significant levels of IFNg, TNFa, and IL-2 when encountering CD19+ ALL cell lines but not CD19– cells. In xenograft models, 3 × 10^6 unselected anti-CD19-CAR T-cells injected via tail vein eliminated engrafted ALL (NALM6 cell line stably expressing both GFP and firefly luciferase, NALM6-GL) within 48 hours in 5/5 immunodeficient NOG mice (Figure 1) whereas all animals that received 3 × 10^6 activated but untransfected T-cells required sacrifice within 18 days. Nearly two months after T cell infusion, CD19-CAR T cells bearing an effector memory phenotype could still be detected in peripheral blood. When lower T cell doses were used, antitumor effects were less potent and were associated with a lack of persistence of anti-CD19-CAR T cells in vivo. CD4+ T cells are not classically cytotoxic and normally require Class II presentation of target peptides for recognition. However, since CAR based recognition is MHC independent, we hypothesized that both CD4+ and CD8+ anti-CD19-CAR T-cells may mediate cytotoxicity. To test this, CD4+ and CD8+ T-cells from the same donor were negatively selected using immunomagnetic beads, then activated and transduced as before. A 4-hour 51Cr release assay demonstrated cytotoxicity from CD8+ CAR T-cells similar to unselected cells but no appreciable cytotoxicity from CD4+ CAR T cells. However, in NOG xenografts, 1 × 10^6 CD4+ CD19-CAR T cells produced complete responses in 4/5 mice by Day 10 as compared to 5/5 complete responses in animals receiving 1 × 10^6 CD8+ CD19-CAR T cells. While antitumor effects mediated by CD8+ T cells were rapid and nearly complete within 3 days, antitumor effects of CD4+ T cells were slower, peaking at approximately day 14. Together, these results demonstrate notable differences in efficacy of anti-CD19-CAR based therapy with small changes in cell dose, unexpected activity of CD4+ anti-CD19-CAR based T cells in xenografts which is not reflected by activity in short term killing assays, and evidence that cure of mice is associated with persistence of anti-CD19-CAR modified T-cells in this model. These results inform clinical development of this emerging therapy by emphasizing the importance of cell dose, cell persistence and the novel observation that CD4+ anti-CAR T cells may be important effectors in mediating antitumor effects of this therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract Case report - Introduction Considering an auto-inflammatory disorder is important where recurrent fevers are a presenting feature. Performing a genetic panel is essential in these cases; however, it can be negative even in the presence of an underlying auto-inflammatory disorder. Our case highlights the importance of this with a reminder that a negative gene panel does not completely exclude an underlying auto-inflammatory disorder in the presence of suggestive history and clinical examination findings. Case report - Case description A 5-year-old girl presented with recurrent episodes of fever (>38 °C), abdominal pain and joint pains (back, wrist, hip, knee & ankle). Past medical history included episodes of self-resolving neutropenia. Initial clinical examination revealed mouth ulcers, a significant number of dental caries, a petechial rash and genital erythema. There was no active joint disease. A pustular like itchy rash developed on/off over time affecting the buttocks, genital area, knees and elbows. Episodes increased in frequency becoming once per month, lasting for 5 days on average, resulting in a significant amount of time off school. Initial differential diagnosis included periodic fever and cyclical neutropenia. White blood cells ranged from 4.3 to 20.1 (10^9/l), Neutrophils ranged from 1.1 to 11.4 (10^9/l), CRP 0.7 to 149.5 (mg/L), ESR 2 to 15 (mm/hr). Serum Amyloid A ranged from 8.0 to 370 (mg/L). Immunology and haematology consults were sought with cyclical neutropenia deemed unlikely. A primary immunodeficiency screen was negative. Initial genetic analysis for periodic fever was negative; however, this was later reanalysed and revealed a pathogenic mutation in the PSTPIP1 gene and a mutation in the TMEM173 gene. A mutation in the PSTPIP1 gene, on chromosome 15q24 is associated with Pyogenic Arthritis, Pyoderma gangrenosum and Acne (PAPA) Syndrome. A trial of colchicine was commenced, with eventual titration of the dose, achieving a good response. Occasional episodes now occur 1—2-times monthly with a reduced temperature rise, minimal arthralgia and are of a shorter duration. Dental extraction was also performed due to 9 periodontal abscesses. Skin care advice included use of emollient-barrier creams, antihistamines and oral antibiotics when indicated. Case report - Discussion PAPA – Pyogenic Arthritis, Pyoderma Gangrenosum and Acne are a triad of symptoms that together combine to form this rare auto-inflammatory disorder. It is an autosomal dominant condition. It is the result of a mutation of the (PSTPIP1/CD2BP1) gene located on chromosome 15. Studies of families affected have revealed a variable penetrance, including some asymptomatic carriers. Clinicians should be mindful when ascertaining what conditions and symptoms other family members have, as PAPA could be the underlying causative condition. The recurrent aseptic inflammation of the joints normally manifests within the first two decades of life. The skin symptoms manifest within the third decade. All three symptoms rarely appear instantaneously. The diagnosis is clinical with confirmation by genetic testing. Reported treatments includes the use of corticosteroids, arthrocentesis – for relieving pain, and biologics – namely anti IL1 and anti TNF therapy. We felt this case was interesting as the patient described demonstrated a good response to colchicine and highlighted the difficulties that can present in making the diagnosis. With a confirmed diagnosis the clinician can then appropriately follow up the patient, giving them and potential family members the best care available. Case report - Key learning points Our case highlights the importance of multi-specialty input particularly when faced with a rare or complex case in order to exclude other potential causes. Although genetic testing has significantly improved in helping with the diagnosis of auto-inflammatory disorders, it must be highlighted the importance of good clinical assessment and interpretation of more standard investigations. This is particularly relevant where genetic panelling is returned as negative and concerns persist of an underlying auto-inflammatory disorder. We hope to raise awareness of the varied presentation of PAPA syndrome particularly in the younger age groups where skin presentations may not be a predominant presenting feature. It is also important to emphasise that the main features of PAPA syndrome rarely present simultaneously. Current clear treatment pathways do not exist due to the rarity of this condition within the paediatric population – a number of agents are suggested in the literature with colchicine achieving good control in our patient described.

La immunodeficiència comuna variable (IDCV) és una alteració immunològica caracteritzada per un defecte de la producció d’anticossos en relació a infeccions sinopulmonars recurrents, trastorns autoimmunitaris, malaltia granulomatosa i augment del risc de neoplàsies. La IDCV és una malaltia heterogènia i els pacients pediàtrics presenten una gran variabilitat clínica i evolutiva atribuïble en part a que es tracta d’un diagnòstic d’exclusió. El present estudi aprofundeix en la descripció clínica, les anàlisis immunològiques i l’estudi genètic (seqüenciació d’exoma complet) d’una cohort de pacients diagnosticats d’IDCV de debut i diagnòstic pediàtric. S’estudien 25 pacients on la mediana d’edat al primer símptoma és de 4 anys i al diagnòstic de 9 anys. La majoria de pacients són de sexe masculí, raça caucàsica i no consanguinis. S’identifiquen característiques clíniques i immunològiques associades a certs fenotips. Els pacients on es detecten mutacions desenvolupen més fenotips clínics i han presentat infeccions per CMV i/o VEB. Més de la meitat dels pacients amb IDCV presenten malaltia autoimmunitària i una tercera part associen 2 o més malalties autoimmunitàries. Les pacients de sexe femení presenten fenotips més complexes i pitjor pronòstic, i els pacients amb expansió dels limfòcits B CD21low presenten major probabilitat d’autoimmunitat. Es diagnostiquen 5 neoplàsies (4 limfomes) en 4 dels 25 pacients pediàtrics amb IDCV. Donat que no hi ha cap fenotip immunològic ni clínic clarament associat amb un increment del risc de desenvolupar malignitat, recomanem realitzar cribratge i prevenció dels factors modificables de càncer en tots els pacients amb IDCV independentment de la seva edat. Endemés, en els pacients pediàtrics amb immunodeficiència i limfoma s’hauria de considerar la recerca de defectes genètics. L’estudi permet diagnosticar de forma més precisa fins el 20% dels pacients gràcies als estudis genètics (mutacions en TACI, LRBA, PIK3R1 i CTLA4). En aquests pacients ha estat possible el consell genètic i en 2 d’ells el fet d’establir un diagnòstic de certesa ha representat un canvi en el tractament i per tant en el seu pronòstic.
Common variable immunodeficiency (CVID) is an immune disorder characterized by a defect of antibody production in relation to recurrent sinopulmonary infections, autoimmune disorders, granulomatous disease and an increased risk of malignancy. CVID is a heterogeneous disease and pediatric patients have a great clinical variability and evolution attributable in part to the fact that it is a diagnosis of exclusion. The present study is focused on the clinical description, the immunological analysis and genetic study (whole exome sequencing) of a cohort of patients diagnosed of CVID with pediatric onset and diagnosis. We study 25 patients where the median age at the first symptom is 4 years old and 9 years old at diagnosis. Most of patients are male, Caucasian race and not inbred. Clinical and immunological characteristics are identified associated with certain phenotypes. Patient with mutations developed more clinical phenotypes and suffer CMV and/or EBV infections. More than half of patients with CVID presented autoimmune disease and 1/3 associated two or more autoimmune diseases. The female patients presented more complex phenotypes and worse prognosis, and patients with expansion of B lymphocytes CD21low presented greater chance of autoimmunity. Five malignancies (4 lymphomas) were diagnosed in four out of the 25 CVID pediatric patients. Since neither a particular immunological nor clinical phenotyping is clearly associated with an increased risk of developing malignancy, we recommend performing screening and prevention of modifiable factors for cancer in all CVID patients regardless of their age. Moreover, in pediatric patients with immunodeficiency and lymphoma, a screening for underlying genetic defects should be considered. This study allows diagnosing more accurately up to 20% of patients because of genetic studies (mutations in TACI, LRBA, PIK3R1 and CTLA4). In these patients has been possible genetic counselling and in 2 of them the fact of establishing a diagnosis of certainty has represented a change in the treatment and therefore in their prognosis.

Au-delà du bénéfice clinique du diagnostic, l'étude des patients atteints de déficits immunitaires héréditaires a aussi largement contribué à la compréhension des mécanismes moléculaires complexes impliqués dans la réponse adaptative humaine contre les pathogènes. Cependant, un grand nombre d’immunodéficiences primaires n’a pas encore été génétiquement défini, en particulier le déficit immunitaire commun variable (ou CVID en anglais). Au cours de ma thèse, j'ai cherché à identifier et caractériser de nouvelles causes moléculaires aux immunodéficiences primaires en me basant sur des mutants naturels humains comme modèle de recherche. Par séquençage entier de l'ADN de patients présentant une forme pédiatrique ou familiale de lupus érythémateux disséminé (ou SLE en anglais) et CVID, nous avons identifié trois variations hétérozygotes distinctes prédites comme délétères chez un patient atteint de CVID (RELAWT/Y306X), un patient pédiatrique SLE (RELAWT/R329X) et les patients atteints de SLE (RELAWT/H86N). Afin de comprendre comment les mutations identifiées peuvent affecter le rôle de RELA dans la voie NF-kB, nous avons confirmé que les deux mutations non-sens de RELA entraînent l'expression de formes tronquées de la protéine, tandis que la mutation faux-sens menait à l'expression de formes mutées de la protéine. Par immunoblot des protéines nucléaires et par immunofluorescence cellulaire, nous avons démontré que les deux formes tronquées de RELA peuvent entrer dans le noyau. Ensuite, en utilisant un oligonucléotide consensus NF-κB marqué, nous avons démontré que les deux formes tronquées de RELA étaient capables de se lier à l'ADN. Les trois protéines RELA mutées, lorsqu'elles étaient exprimées de manière ectopique, présentaient une altération de l'activité transcriptionnelle. Enfin, nous avons montré par co-immunoprécipitation que les trois protéines RELA mutées exprimées de manière ectopique sont capables d'interagir avec ses partenaires protéiques et de former des homodimères. En conclusion, nos résultats indiquent que des mutations affectant le facteur de transcription RELA peuvent être associées à des CVID ou des SLE. Étant donnés les cas précédents décrivant des haploinsuffisances de RELA liées à un syndrome lymphoprolifératif avec auto-immunité associé à une cytopénie auto-immune ainsi qu’aux ulcérations cutanéo-muqueuses TNF-dépendantes associées à des inflammations intestinales, notre travail élargit le spectre des maladies et des phénotypes cliniques liés à un dysfonctionnement de la protéine RELA et suggère que différentes mutations du gène RELA entraînent diverses conséquences fonctionnelles
Beyond the clinical benefit for diagnosis, the study of patients with primary immunodeficiency (PID) has also largely contributed to the deciphering of the complex molecular mechanisms involved in the human adaptive response against pathogens. Still, a large number of PIDs, especially common variable immunodeficiency (CVID), are genetically not defined. During my thesis, I aimed to identify and characterize novel molecular causes of PIDs based on human natural mutants as a research model (1). By whole-exome sequencing of DNA from patients presenting either with pediatric or familial form of CVID and Systemic Lupus Erythematosus (SLE), we identified three distinct heterozygous single nucleotide variations predicted deleterious in a CVID patient (RELAY306X), a pediatric SLE patient (RELAR329X) and familial SLE patients (RELAH86N). To better understand how the identified mutations may impact the role of RELA in the NF-kB pathway, we confirmed that the two nonsense RELA mutations led to the expression of truncated forms of the protein, while the missense mutation led to the expression of mutated forms of the protein. By immunoblotting of nuclear protein extracts and cellular immunofluorescence, we demonstrated that the two truncated forms of RELA can translocate into the nucleus. Then, using a labeled NF-κB consensus oligonucleotide, we demonstrated that the two truncated forms of RELA were able to bind to DNA. All three mutated RELA proteins, when expressed ectopically, had an impaired transcriptional activity. Finally, we showed by immunoprecipitation that all three ectopically expressed mutated RELA proteins are able to interact with protein partners and form homodimers. As a whole, our results indicate that mutations affecting the transcription factor RELA can be associated with CVID or SLE. Given the previous cases associating RELA haploinsufficiency to autoimmune lymphoproliferative syndrome with autoimmune cytopenia and to TNF-dependent mucocutaneous ulceration and inflammatory intestinal disease, our work widens the spectrum of disease and clinical phenotypes associated with RELA dysfunction and suggests that different RELA mutations lead to different functional consequences

Introdução: A Imunodeficiência Comum Variável (ICV) faz parte de um grupo de imunodeficiências primárias na qual os pacientes apresentam defeitos na maturação e diferenciação dos linfócitos B (LB), resultando em distúrbios funcionais além de alterações na distribuição de seus subtipos. Consequentemente, estes pacientes apresentam hipogamaglobulinemia, susceptibilidade a infecções e ausência de produção de anticorpos a antígenos específicos. Na tentativa de reduzir os episódios de infecções recorrentes, alguns trabalhos têm recomendado a vacinação com patógenos mortos ou subunidades e em trabalho anterior demonstramos a eficácia clínica da vacinação de pacientes com ICV, porém, a experiência com a administração de vacinas em imunocomprometidos é limitada. Objetivos: Avaliar a cinética da distribuição das subpopulações de linfócitos B antes e após a vacinação com antígenos proteicos e polissacarídicos em pacientes com ICV acompanhados no Ambulatório de Imunodeficiências Primárias do Hospital das Clínicas, FMUSP, além da produção de anticorpos específicos aos antígenos vacinais. Pacientes e Métodos: Um grupo de 35 pacientes com ICV e 16 controles foram vacinados contra Influenza, H1N1 e S. pneumoniae. Após as coletas nos tempos pré e pós 1, 3 e 6 meses foram realizados a separação de PBMC e cultura de linfócitos com lisado viral e hemaglutinina de Influenza, além da citometria de fluxo para identificação das subpopulações de LB naive, zona marginal (MZB), memória com troca de isotipo (SMB) e plasmoblastos (PBL). Foram dosados os anticorpos específicos e no grupo dos pacientes foi aplicado um score de sintomas antes e após a imunização. Resultados: Apesar da redução significativa na pontuação do score de sintomas, a maioria dos pacientes não produziu anticorpos específicos para Influenza, H1N1 e S. pneumoniae. A análise da cinética das subpopulações de LB revelou que em indivíduos saudáveis, a resposta contra Influenza apresentou duração de 6 meses, observada por meio da redução da subpopulação naive e aumento gradual da frequência de SMB a partir do primeiro mês. Observamos também redução da população de memória por volta do 3º mês, com aumento da população de PBL que permaneceu elevada até o 6º mês. Por outro lado, a despeito de os pacientes apresentarem aumento de SMB no primeiro mês após a vacinação, sua frequência foi inferior ao observado nos controles, decaindo ao terceiro mês. A população de PBL apresentou aumento precoce no primeiro mês após a vacinação, também muito menor do que observado nos controles, não sendo mantido no terceiro mês. Ainda, observamos uma correlação entre o aumento da expressão destas duas subpopulações no primeiro mês. Apenas a população de MZB apresentou aumento significativo no terceiro mês nos pacientes quando comparados aos controles. Ao dividirmos os pacientes de acordo com a expressão de SMB e PBL após 1 mês da administração das vacinas, observamos que os pacientes que apresentaram aumento na expressão de células B de memória foram os que exibiram uma melhora clínica mais expressiva, soroconverteram e desenvolveram soroproteção para H1N1.Conclusões: Apesar de não apresentarem eficaz diferenciação em células de memória e efetoras, resultando na resposta precoce e de curta duração, observamos que os pacientes foram capazes de reconhecer e responder às vacinas. Além disso, a elevada expressão de MZB no terceiro mês após a vacinação pode sugerir a atuação desta subpopulação na apresentação para os LT. Estes achados reforçam a necessidade de uma melhor compreensão da ativação do sistema imune em pacientes com ICV, para uma adequada subdivisão de acordo com o perfil de resposta após a vacinação
Introduction: Common Variable Immunodeficiency (CVID) is a primary antibody deficiency characterized by defects in B lymphocyte maturation, resulting in disturbed differentiation, distribution and functional variations on its subtypes. As a result , CVID patients have hypogammaglobulinemia and poor antibody response to specific antigens with increased susceptibility to infections. In an effort to minimize the recurrent episodes of infections, some studies have recommended immunization with inactivated pathogens or subunits and in a former study we have shown the clinical improvement determined by immunization in CVID patients, but the experience with vaccines\' administration to immunodeficient patients is limited. Objectives: To evaluate the changes in distribution of B cell subtypes before and after vaccination of CVID patients followed at the Division of Clinical Immunology and Allergy of University of São Paulo Medical School with protein and polysaccharide antigens, as well as specific antibody production . Methods: A group of 35 CVID patients and 16 controls were vaccinated against Influenza, H1N1 and S. pneumoniae vaccines. Blood samples were collected before and 1, 3 and 6 months post vaccination. PBMCs were stimulated with Influenza viral lysate and hemagglutinin peptide. Flow cytometry was performed to identify naïve B cells, marginal zone (MZB), switched memory B cells (SMB) and plasmablasts (PBL). Specific antibody production was measured and a symptoms score was applied for clinical evaluation before and after immunization. Results: In spite of the significant reduction in symptoms score after vaccination, most patients didn\'t produce specific antibodies to Influenza, H1N1 and S. pneumoniae. The analyzes of B cell subtypes changes in healthy individuals upon in vitro Influenza stimulation showed that the response endured up to 6 months post immunization. We observed a reduction in naïve B cell frequency while gradual increase in SMB frequency occurred already at 1 month after vaccination. Moreover, as the memory cell population declined, PBL population increased at the third month post vaccination until the sixth month. Although patients had an increase of SMB on the first month after vaccination, it was lower than that observed in controls, decreasing by the third month post vaccination. Plasmablast frequency had an early increase on the first month, also much lower than the observed in controls decreasing by the third month. In addition, we observed a correlation between the increased expression of SMB and PBL on the first month post vaccination. In patients, only MZB subtype presented a significant increase on the third month when compared to controls. We divided the patients according SMB and PBL expression after 1 month post vaccination and we observed that patients who were able to produce memory B cells showed a better clinical improvement, developed H1N1 seroconversion and seroprotection. Conclusion: Despite the defect on differentiation into memory and effector B cells resulting in early response with lowduration, we observed that patients were able to recognize and respond to vaccines. In addition, the over expression of MZB on the third month after vaccination may suggest the role of this subpopulation as an antigen presenting cell for T cells. These findings reinforce the need of a better understanding of immune system activation and response in CVID patients to propose a division according to vaccine (antigen) responders and non responders