INMUNOPATOLOGY

Author: MUÒâOZ RODRҍGUEZ FRANCISCO JOSE.
Year: 2003.
University: BARCELONA.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: FACULTAD DE MEDICINA.

Summary: En la Tesis Doctoral se establecen tres objetivos fundamentales: profundizar en el conocimiento de las caracterÃÂsticas clÃÂnicas del sÃÂndrome antifosfolipÃÂdico, estudiar el papel de los anticuerpos antiprotrombina en su fisiopatologÃÂa y analizar la resistencia adquirida a la acción de la proteÃÂna C activada como un posible mecanismo de the thrombosis associated with the antibodies antifosfolipÃÂdicos. For respoder these objectives are diseÃÂ ± aron three studies. The first was a study clÃÂnico in which analyzed the caracterÃÂsticas clÃÂnicas and evolution of 100 patients diagnosed with sÃÂndrome antifosfolipÃÂdico with a median follow-up time of 49 months. It observÃÂ ³ that patients with a history of thrombosis have a high risk of recurrence and that the anticoagulaciÃÂ ³ n orally administered indefinitely is the best prophylaxis; ademÃÂ ¡s, administraciÃÂ ³ n treatment profilÃÂ ¡ctico during pregnancy in patients with the aforementioned sÃÂndrome considerably reduces the likelihood of abortions or pÃÂ © rdidas fetal. The second study estandarizÃÂ ³ a tÃÂ © cnica ELISA for detecciÃÂ charges of antibodies antiprotrombina and estudiÃÂ ³ its presence in a series of 177 patients with sÃÂndrome antifosfolipÃÂdico primary or lupus erythematosus sistÃÂ © mico. It won an overall prevalence of 47%, significantly higher than that observed in the control group consisting of 87 healthy volunteers (5%). AdemÃÂ ¡s in patients with lupus erythematosus sistÃÂ © mico its isotipo IgG is an independent risk factor for the development of thrombosis. Finally, the third study analizÃÂ ³ acquired resistance to acciÃÂ charges of proteÃÂna Activated Protein C, one that was not due to the presence of factor V Leiden, in 103 patients with lupus erythematosus sistÃÂ © mico and 103 healthy volunteers. First they observÃÂ ³ that the presence of factor V Leiden was low and similar to poblaciÃÂ ³ n overall (4%). The acquired resistance alcanzÃÂ ³ prevalence approximately 20% and asociÃÂ ³ significantly with the presence of antibodies antifosfolipÃÂdicos, especially with the isotipo IgG antibodies antibodies and antiprotrombina. By ÃÂ seventh last her presence asociÃÂ ³ with a higher prevalence of arterial thrombosis and failed pregnancies.

Author: ARNEDO VALERO MIREIA.
Year: 2003.
University: BARCELONA.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: HOSPITAL CLҍNIC DE BARCELONA.

Summary: The inability to eradicate the human immunodeficiency virus (HIV-1) of the human organism with the pattern terapÃÂ © uticas high efficiency (HAART), adherence to standards terapÃÂ © uticas complex and the risk of a significant toxicity farmacolÃÂ ³ gica acute and crÃÂ ³ nica , are the main problems in the administraciÃÂ ³ n extended the fÃÂ ¡rmacos antiretrovirals. It iminente the need for diseÃÂ ± ar new treatment strategies and in this regard have been developed therapies inmuno-mediadas, an example being structured treatment interruptions (ETT), aimed at controlling the replicaciÃÂ ³ n dell HIV on the basis of recuperaciÃÂ ³ n the immune response especÃÂfica. Against this background, the study virolÃÂ ³ gico of dinÃÂ ¡mica and evoluciÃÂ charges of HIV along the different treatment interruptions structural, permitirÃÂ Do a better understanding of the observed changes in the replicaciÃÂ ³ n viral during the period of the ETT, either because factors inmunolÃÂ ³ ments, virolÃÂ ³ ments, or both, this will determinÃÂ ³ the dinÃÂ ¡mica viral during ETT and its relaciÃÂ ³ n response to the T cell HIV-1 especÃÂfica in a group of patients undergoing ETT, in a group of patients undergoing ETT and a immunomodulador, hydroxyurea and in a group of patients undergoing ETT and an immunosuppressant, ÃÂ ¡cido micofenÃÂ ³ lico. TambiÃÂ © n is realizÃÂ ³ a study of evoluciÃÂ ³ n of the virus in the first group of patients. By ÃÂ fourth Finally, the study of the resistance mutations in these patients ayudarÃÂ ¡na determine the risk that can result from the aplicaciÃÂ ³ n of this therapy to prÃÂ ¡ctica clÃÂnica. The results obtained in the anÃÂ ¡lysis of the dinÃÂ ¡mica virus were in all patients observÃÂ ³ a resurgence of viral load in each of the interruptions of therapy. Significantly were observed attenuation in significant regrowth of viral load along the ETT. Some 25% of patients had values estabilizaciÃÂ ³ n viral load less 5000 copies / ml for a median of 52 weeks of the ÃÂ seventh last interrupciÃÂ charges, which observÃÂ ³ an increase in cellular immune especÃÂfica front response to HIV-1. In all of the patients were achieved undetectable viral loads once reintroduced treatment. The results obtained in the evoluciÃÂ ³ n genÃÂ © tica virus along the ETT not observÃÂ ³ a trend of homogenizaciÃÂ charges of cuasiespecies viral. There were no significant differences in variability genÃÂ © tica virus among patients with the ability or not to neutralize replicaciÃÂ ³ n viral. On the other hand if detectÃÂ ³ the reactivaciÃÂ charges with the consequent re-emergence of old ancestral provirus in the resurgence of viral load as a result of the interrupciÃÂ ³ n treatment. In considering the risk of selecciÃÂ charges of resistance mutations during the ETT was observÃÂ ³ a 26% patients had genetic mutations, of which half the selected novo during the period of the ETT. Of these patients 23% had mutations de novo to inhibitors of trasncriptasa inverse not anÃÂ ¡logos nucleÃÂ ³ sidos (ITIANN), 12% by reverse transcriptase inhibitors anÃÂ ¡logos nucleÃÂ ³ sidos (ITIAN). There were detected resistance mutations to inhibidotes of protease (IP). The risk of selecciÃÂ charges of resistance mutations was higher than ITIANN due to the long half-life of these fÃÂ ¡rmacos, a fact that should be taken into consideration when undertaking such a strategy terapÃÂ © utica.

Author: MARTINEZ LOSTAO LUIS.
Year: 2004.
University: AUTÓNOMA DE BARCELONA.
Place of defense: FACULTAT DE MEDICINA.
Place of preparation: ESCUELA DE POSTGRADO UAB.

Summary: The path JAK / STAT is involved in various events such as cellular differentiation, proliferation, cell survival and apoptosis. However, the aberrant activation of STAT gives rise to several sitauciones pathological, inlcuida the oncogénesis. The implication of the way JAK / STAT oncogénesis has been widely studied. The STAT are constituivamente activated in a variety of human cancers, including a number of leukemias. The Chronic Lymphocytic Leukemia B cell (LLC-B), the most common leukemia in the Western world, is characterized by the accumulation of mature CD5 + B cells arrested at the stage of G0/G1 cell cycle. There are strong indications that LLC-B is related to defects in apoptosis. Both defects in apoptosis. Both genetic defects such as external stimuli affect the abnormal behavior of these cells. Fludarabina (F-ara-A) is an analogue of adenosine resistant to adenosine deaminasa widely used in the treatment of LLC-B. Although the main action F-ara-A is inhibition of DNA synthesis, it has demonstrated its therapeutic action in LLC-By other categories lymphoproliferative indolent with very low rate of proliferation. It has been described by other mechanisms of action for F-ara-A, but the exact mechanisms by which fludarabine kills cells LLC-B are not clear. The specific inhibition of signaling by sTAT1 has been involved in the effect of fludarabine in LLC-B. It has been described that fludarabine inhibited specifically STAT1 removing the ability of cells to respond to interferons. Therefore, although it has not been observed phosphorylation in tirosinas of STAT1 in cells without stimulating patients with LLC-B, STAT1 could be an important factor in the transmission of signals antiapoptóticas in LLC-B. This justifies the study of other drugs capable of blocking activation of STAT1, as inhibitors JAK kinases AG490 and WHI-P131 for use as therapeutic agents in LLC-B. In this paper, we analyze the ability of fludarabine, a known inducer of apoptosis in cells LLC-B, and two JAK kinase inhibitors, AG490 and WHI-P131, to block the activation STAT1 in the cells. Our data show that while all drugs induced apoptosis in LLC-B analyzed, only AG490 and WHI-P131 inhibited significantly activating STAT1 by interferon in cells LLC-B. Despite its longevity in vivo, cells LLC-B suffer often a spontaneous apoptosis in vitro. This means that the programmed cell death of cells LLC-B cultivated resulting from the absence of signals essential to survival. These signals can come from external other cell types either by the production of growth factors or by contact célula-célula. Among the cells involved in the in vitro survival of the LLC-B, has described a subgroup of cells derived from peripheral blood can differentiate spontaneously in vitro. These cells expressing markers of acceding ilk monocítica and protect cells LLC-B of spontaneous apoptosis cells play a role as "marselike cells (NLCs). To learn about the mechanisms involved in the antitumor effect of fludarabine in cells LLC-B, we studied the effect of fludarabine in NLCs and its impact on the viability of the cell LLC-B making crops Crusaders. Our data show that fludarabine can block the development of NLCs growing and induce the death of NLCs diferenciad 8 as cuand 373 or allowed their growth and fludarbina induce apotosis in vitro cell LLC-B mainly by action direct on these tumor cells.

Author: KOLKOWSKI EDGARDO CARLOS.
Year: 2004.
University: AUTÓNOMA DE BARCELONA.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: ESCUELA DE DOCTORADO Y DE FORMACIÓN CONTINUADA.

Summary: Celiac disease (CD) is a chronic inflammatory disease that is induced in genetically susceptible patients after ingestion of gluten, which affects the lining of the small intestine. This inflammatory process appears to be triggered by T lymphocyte CD4 + lamina propria specific gluten and for the development of Ac's anti Tranglutaminasa. The condition is also associated with an increased lymphocyte Intraepiteliales (IELs). The IELs are cells CD8 + TCRalfabeta or ** expressing integrina alfaE (ED103) beta7. While might have antitumor activity, recognize viral antigens, participate in the maintenance of homeostasis and exercise activities suppressor, it is not known their real physiological role, both at mucusa normal as pathological. The increase of IELs in celiac disease suggests a role in the destruction of the epithelium or its regulation. The purpose of this study was to determine the caraceterísticas phenotypic and functional IELS * beta CD8 + and gamma * expanded in vitro aprtir of biopsies from patients celíacas and donors not celiac. This characterization included the study of cytokine profile following in vitro stimulation of the TCR, the opposite pattern recognition epithelial cells and the search for markers membrane, enabling us to identify sutipos of IELs involved in the development of the disease. The results show a significant degree dehterogeneidad within populations of IELs literate and gamma *. The cytokine profile indicates that the production of IL-10 and IL-2 by IELs literate CD8 + CD103 + specific epithelium would be unbalanced and would play a role in developing the disease, since clones CD are mostly non-producing d eIL-10 but secrete IL-2, contrary to what happens with celiac not clones. The cells gamma * show a profile Th1/citotóxico associated with a regulatory function in some of the clones. Some clones gamma * recognize epithelial ligands expressed in terms of stress. Others showed a phenotype deiferente without cytotoxic activity against epithelium and synthesis of regulatory cytokines including IL-10, IL-4 and IL-5. None produced IL-2 in contrast to IELs literate CD8 +. Recognition of epithelial cells was mediated in many cases by the TCR and was independent of the interaction NGK2D/MICA. Such interaction would be important in cases of refractory celiac condition, as demonstrated by other authors. In conclusion, we propose that in physiological conditions, IELs CD8 + producers of IL-10 control inflammatory processes expected in the mucosa, as a synthesis of IL-2 and other factors involved in the destruction of the matrix of the lamina propria. In celiac disease, IELs CD8 + producers of IL-2 would be involved in the damage of the epithelium. As for the gamma * cells, epithelial reactivity with those involved in the control of enterocytes stressed that while the regulatory cells, non-cytotoxic control epithelial homeostasis.

Author: ROSADO GARCÍA SELVIA.
Year: 2004.
University: AUTÓNOMA DE MADRID.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: HOSPITAL UNIVERSITARIO CLÍNICA PUERTA DE HIERRO.

Summary: There are data in the literature related to excessive production of interleukin 10 (IL 10) with certain alterations in the immune lupus erythematosus sitémico (LES), and even with its pathogenesis. It is also well known that in the production of this cytokine inherited factors involved, so that various studies have attempted to evaluate the usefulness of certain polymorphisms of the gene for IL-10 as a marker of disease. The data are controversial, possibly because there are many factors in modulating the production of IL-10 that hamper the study of the direct involvement of the gene. In this paper we have studied the association of the genetic variability of the promoter of IL-10 with LES in Spanish population and has tried to analyze the physiological basis of the same. It documents the LES partnership with the polymorphisms of pormotor of IL-10 located at positions -1082, -819 and -592. Some combination of variants in these positions (GCC) is described as inducing disease and clinical features present in some patients. In addition, this partnership is supported by the finding of a higher level of serum cytokine in patients carrying this haplotype. This relationship is not changed, nor with the population studied, not with the degree of activity of the disease itself, as it is also in the healthy controls. Therefore, consistent with the data públicados, pointing to the GCC as high haplotype producer of messenger RNA of IL-10 in healthy subjects, the present study provides new data complementary, since it describes how this relationship is also extensible production protein in Patients with LES. Furthermore, data were provided novel approaches to the expression of the molecule HLA-G in skin biopsies of patients with LES, pointing to a possible role inmunorregulador of this protein in this disease.

Author: PEREZ CHACON GEMA.
Year: 2004.
University: AUTÓNOMA DE MADRID.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: FUNDACION LAIR.

Summary: The chronic lymphoid leukemia B cells (LLC-B) is the most common leukemia in the Western world. It is characterized by clonal expansion of B lymphocytes CD5 + it accumulates slowly and gradually in the blood, can infiltrate bone marrow, lymph nodes and spleen. Clinically, patients have a very heterogeneous development, as they are distinguished patients with a prolonged survival and not requiring treatment over other with a rapid development of the disease and resistant to therapy. Currently it is thought that this heterogeneity is due to the different response to the cell tumor antigen. It is known that the response to antigen depends on the functionality specific antigen receptor (BCR), as well as additional signals of glycoproteins moduladolas associated with it. These include the CD5, which functions as a negative regulator of the BCR signaling path. In this work, we studied the relationship enrte molecule CD5 and clonal expansion that characterizes this disease. It was noted that unlike in B cells healthy, the signs of viability, apoptosis and proliferation in response to stimuli anti-BCR not affected by the absence of CD5 in tumor cells. This seemed to indicate that CD5 not exerted an inhibitory effect on the signaling initiated through the BCR in these cells, a fact that may be related to tumor growth. However, this lack of modulation did not appear due to defects in the way of signaling CD5, since antibodies anti-CD5 induced apoptosis or viability depending on the dose of antibody used. CD5 was capable of shooting events as the immediate activation of protein tirosinas kinase phosphorylation and the subsequent induction of protein antiapoptótica Mcl-1, a path-dependent activation of protein kinase C (PKC). Moreover, this signaling via CD5 also boosted the production of interleukin 10 (IL-10), immunomodulatory cytokine that could also participate in maintaining the viability of the tumor cells.

Author: SEGARRA BLASCO MARTA.
Year: 2005.
University: BARCELONA.
Place of defense: FACULTAD DE MEDICINA.
Place of preparation: FACULTAD DE MEDICINA.

Summary: The metaloproteasas matrix (MMPs) are enzymes highly relevant biological processes related to the reorganization of the extracellular matrix and are also involved in the regulation of various cellular processes controlled by signals microentonro cell. The limfocitos produce small quantities of gelatinasas (MMP2 and MMP9), which are essential for migration through the fabric, both in physiological situations as pathological phenomena in inflammation and tumor spread. The extracellular matrix proteins, by binding to receptors integrina is one of the most powerful mechanisms not only in production but also in the activation of gelatinasas cells limfoides T. However, the mechanisms that modulate the production of MMPS through integrins in limfocitos not identified. This thesis consists mainly of 3 work which explores the production of gelatinasas by limfocitos in different aspects. On the one hand, we describe the mechanisms of signaling mediated by receptors integrina that regulate the production and secretion of MMPs in response to stimuli of the microenvironment (extracellular matrix proteins). On the other hand, we study the pathophysiological implications of these results in an inflammatory process invasive (giant cell arteritis) and a neoplastic process (disorders limfoproliferativos). Based on the results we have reached the following conclusions: 1 - The signaling through integrins in response to stimuli of the microenvironment (notably fibronectin) is a very efficient mechanism for the production and activation of gelatinasas (MMP2 and MMP9) and MMP14 so limfocitos Ty B. 2, fibronectin-binding leads to a post-liberation rapid gelatinasas in these cells. The secretion of this enzyme is necessary for the process and invasion. 3 - The mechanisms of signaling integrina are modulated by FAK (Focal accession kinase) and its interaction with Src tirosina-quinsas. FAK, through the coupling of dual signals, coordinates the release of gelatinasas and processes necessary for accession cyclical migration, suggesting that FAK adapt pulsatile secretion of gelatinasas to changes in the cytoskeleton in the process invasive limfocitario. 4 - inflammation of the arteries of patients with giant cell arteritis is accompanied by an increased expression and activation of gelatinasas and is related to the topographic expression of integrins leucocitarias. This suggests that the progression infiltrated limfocitario is linked to the expression and activation of gelatinasas, which also contribute to the destruction of arterial structure. Treatment with steroids decreases the expression of MMPs. 5 - The thalidomide reduces production geltainasas induced fibronectin cell limgoides B interfering in different signaling pathways mediated by integrins. This could be a genetic mechanisms of action of this drug that explain its effectiveness in the treatment of multiple myeloma in the context of marrow microenvironment. As a general conclusion, the integrins leucocitarias can coordinate production gelatinasas with the mechanisms of cell migration, favoring the invasion. The processes inflmatorios and tumor using this mechanism, and its disruption could benefit from therapeutic developments such pathologies.

Author: ALONSO GIL ROBERTO.
Year: 2005.
University: AUTÓNOMA DE MADRID.
Place of defense: UNIVERSIDAD AUTONOMA DE MADRID - DEPARTAMENTO DE BIOLOGÍA MOLECULAR.
Place of preparation: UNIVERSIDAD AUTÓNOMA DE MADRID - DEPARTAMENTO DE BIOLOGÍA MOLECULAR.

Summary: At the start of the immune response specific antigen recognition conducted by the complex antigen receptor (TCR) T cells leads to the activation, proliferation and cell differentiation T. The stimulation of the TCR also has the potential to induce cell death by apoptosis mediated by the interaction Fas / FasL, a process known as activation-induced cell death or IACD (English "Activation Induced Cell Death"). The death Fas receptor is a membrane glycoprotein widely expressed on thymocytes, and tumor cells TyB normal. Their physiological ligand, FasL, is a membrane protein that is expressed predominantly in activated T cells, cytotoxic T lymphocytes, neutrophils and activated NK cells. The TCR stimulation induces an increase in the second messenger diacilglicerol (DAM) and intracellular calcium (Ca2 +). The DAG induced activation of the protein kinase C (PKC) activation of the path Ras/ERK2 and the cascade of MAP kinase (MAPK). These signaling pathways induce the expression of proteins involved in the activation of T lymphocyte (CD69, IL-2 and IL2-R), as well as apoptosis by IACD (expression of Fas and FASL). The enzyme diacilglicerol kinase (DGK) is expressed in high levels in T lymphocytes Upon TCR stimulation, DGK catalyzes the phosphorylation of DAG to phosphatidic acid (PA), decreasing levels of DAG and avoiding a prolonged signaling through DAM. The DGK is one of the negative regulators involved in the attenuation of responses of T lymphocyte activation mediated by the way DAM / Ras. The activation processes or death from IACD induced after TCR stimulation presented second messengers and signaling pathways common: increased intracellular calcium and activation of the road DAM / PKC / Ras / MAPK. In this regard, it has studied the role of the route DAM / DGK in controlling death from IACD in lymphocyte T. The expression of DGK inhibited IACD mediated by Fas / FasL, whereas inhibition of DGK potentiate the IACD. The regulation of the levels of DAG by DGK (and therefore the road signaling DAM / PKC / Ras / MAPK) did not affect the transcriptional control or traduccional of FasL-induced after stimulation receiver. One of the mechanisms which takes place at the ACID mediated by Fas / FasL on activated T lymphocytes involves extracellular secretion in the middle of exosomas containing FasL. These exosomas are formed by internal membrane invagination into the lumen of endosomas type late, resulting in the formation of bodies multivesiculares (MVB). After stimulation of T lymphocyte triggering release to the outside of these exosomas with cellular FasL, which possess capability of inducing apoptosis mediated FasL / Fas. The activity of the DGK affected IACD FasL-mediated at a level post-traduccional, which analyzed the role of DGK in the secretion of these exosomas with FasL. The expression of DGK inhibit secretion exosomas with FasL, inhibiting apoptosis mediated by these exosomas. Inhibition of DGK enhanced secretion of these exosomas and increased apoptosis mediated by them. Therefore the DGK would regulate the process of secretion exosomas with FasL. The intracellular localization of the DGK showed that it is associated with the trans-Golgi apparatus (TGN), as well as endosomas late. Inhibition of DGK prompted increased translocation of protein kinase D (PDK) to the TGN, altering the dynamics of blistering, training endosomas late / MVBs and location of DGK in these structures. These facts suggest the possible involvement of DAG and DGK during the process of blistering conducted by the KDP in the TGN and / or during the subsequent generation and formation of MVBs, can affect the release of exosomas with FasL and the subsequent induction of apoptosis.

Author: SANCHEZ GARCIA Ma. LUZ.
Year: 2005.
University: SALAMANCA.
Place of defense: CENTRO DE INVESTIGACION DEL CANCER.
Place of preparation: FACULTAD DE MEDICINA.

Summary: The analysis inmunofenotípico of leukemic cells is helpful for investigation of minimal residual disease (EMR) in acute leukemia, but has not been explored its usefulness in chronic lymphoproliferative syndromes B (SLPC-B). The SLPC-B usually derived from a cell monoclonal; occasional cases have been reported from biclonalidad. There are also patients with two subpopulations of células-B with different DNA content whose nature is unknown. The objectives of this study were to investigate the incidence of aberrant phenotypes in SLPC-B, evaluate sensitivity to detect immune EMR, explore frequency biclonalidad and criteria to differentiate biclonalidad evolution intraclonal. We included 514 patients with different SLPC-B. Morphological studies were conducted, inmunofenotípicos, molecular and FISH. We compared two groups of patients: one with two different populations células-B phenotypically and another two populations células-B with phenotype similar but different DNA content and / or values of different size / granularity. The 98% of SLPC-B showed aberrations phenotypic (asincronismos antigenic: 92%; overexpression antigenic: 54%; aberrant values size / granularity: 17%). The 90% had> 4 aberrations phenotypic. Experiments dilucionales showed a sensitivity of the immune> 10-4. Approximately 5% of SLPC-B had two populations of B cells phenotypically distinct and proved biclonales by molecular studies. The cases with chronic lymphocytic leukemia (CLL) were less counting of leukocytes and lymphocytes, higher incidence of spleen and required treatment early. In cases with two populations células-B with phenotype similar but different DNA content, population hiperdiploide was associated with chromosomal alterations regarding the additional population diploid, the molecular analysis confirmed monoclonality. In conclusion, the immune is a sensitive technique for detecting EMR in SLPC-B. The presence of biclonalidad is a normal finding and treating these patients require more frequently. When the two populations show different DNA content but a similar phenotype represent evolution intraclonal.

Author: ZÁRATE HERNÁNDEZ MARÍA DEL CARMEN.
Year: 2006.
University: AUTÓNOMA DE BARCELONA.
Place of defense: UNIDAD DOCENTE DEL HOSPITAL VALL D HEBRON.
Place of preparation: DEPARTAMENTO DE BIOLOGÍA, FISIOLOGÍA E INMUNOLOGÍA.

Summary: The Common variable immunodeficiency (IDVC) is the primary immunodeficiency (IDPs) sintómatica more frequent. Patients with IDVC present a clinical phenotype (recurrent infections, etc.). Immune phenotype and (hypogammaglobulinemia null responses and antibody). The diagnosis of IDVC is done by excluding other causes of hypogammaglobulinemia. The existence of atypical cases, the overlap with other phenotypes of IDPs and the absence of laboratory tests specific IDVC difficult to conduct a correct differential diagnosis. Recently, we have described some defects monogénicos (ICOS, CD19, TACI and BAFFR) related IDVC (10% patients with IDVC). In the present work we studied: a screening method (expression of btk, lck and SAP), the association between the B cell memory and gravity / clinical evolution and the role of ICOS as a genetic cause of the IDVC. The study of the expression of btk, lck and SAP was performed using western blot (n = 55 pacientes-ICVC, 37 men and 18 women, half 36.6a). The protein extract was obtained from PBMC with NP-40 in reductive terms, electrophoresis was performed in Gels pliacrilamida of 4-12%, the transfer system semi-seco in nitrocellulose membrane, used primary antibodies (anti - - btk: ac.mono. BD-Transduction laboratories, anti-lck: ac.mono. DB-Pharmingen, anti-SAP: ac.policlonal rabbit (K. Nichols) and inmunodetección with a substrate Quimioluminiscente (SuperSignalR West Pico ). Of all the patients studied only in one patient the expression of the band btk was negative, formed by studying the Btk intracellular monocytes by flow cytometry and genetic analysis (P597L). The expression of LcK and SAP was normal in all patients. were studied subpopulations of linfoctios B memory (CD19CD27) by flow cytometry (GACSCalibur) in 41 adult patients (21 men and 20 women, average: 37th) and calsificaron into 3 groups: 1 .- Group MB2 includes patients with a number of LB memory (CD19CD27 IgD-) and no change of isotipo (CD19CD27IgD) within the reference values, n = 7) 2 .- Group BM1 includes patients with a significant reduction CD19CD27IgD- increased 6%, n = 16. 3 .- Group BM0 includes patients who have a reducicón significant of the two types of memory LB (CD19CD27 increased 13%), n = 18. There was an association between the defect LB memory and the phenotypic severity clinic patients. The group BM0, 55% of patients with recurrent respiratory infections, developed bronchiectasis with expectoration usual, compared with 27% of patients in group BM1 and 0% of BM2 (p less 0.05). The group BM0. The 50% of patients with gastrointestinal symptoms, developed the malabsorption syndrome, compared with 19% of the group BM1 and 0% of BM2 (p less 0.05%). Signs of linfoproliferaicón were more frequent in the group BM0 (50%) than in group BM1 (16%) and BM2 (14%) (p less 0.05). We analyzed the expression of ICOS in the membrane of T lymphocytes assets (48h with WFP ionomicina) anti-ICOS-FITC C398.4A (JRojo) FACSCalibur) IDVC in patients with a family history of IDPs and / or autoimmune diseases (4 families n = 13). We found no ninguan alteration to enl expression of this molecule in the patients studied. In conclusion, although the diagnostic error found in our study is small and frequency of ICOS is very low that we believe should be included in the algorithm of work to support a system diagnostic screening should include estuido protein associated with IDP phenotype of IDVC. The partnership between alteraicon inmunofenotípica B (BM0. BM1. BM2) and severity denotípica clinic justifies the inclusion of determianción of LB memory in the immune routine study of patients with IDVC.