Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5- and Cd6-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD’s clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders.

Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients.

IMPORTANCE:Variability in genes encoding proteins involved in the immunological pathways of biological therapy may account for the differences observed in outcomes of anti–tumor necrosis factor (TNF) treatment of psoriasis.OBJECTIVE:To assess the role of 2 Fcγ receptor (FcγR) polymorphisms in the response to anti-TNF therapy in psoriasis.DESIGN:Retrospective series of patients with psoriasis who received anti-TNF therapy(infliximab, adalimumab, or etanercept) from January 1, 2007, through December 31, 2010. Patients were followed up for 12 weeks.SETTING:Two psoriasis referral centers.PARTICIPANTS:Seventy treatment-naive patients with moderate to severe psoriasis who received anti-TNF agents.INTERVENTION:Patients underwent FcγRIIA-H131R and FcγRIIIA-V158F polymorphism genotyping.MAIN OUTCOMES AND MEASURES:The Psoriasis Area and Severity Index and the body surface area were assessed at baseline and at treatment weeks 6 to 8 and 12. The polymorphism genotypes were correlated with the treatment outcomes.RESULTS:Bivariate analysis showed a nonsignificant association between FcγR low-affinity genotypes and greater improvement in the Psoriasis Area and Severity Index and body surface area at the end of treatment. Conversely, patients harboring high-affinity alleles presented a greater reduction in body surface area at the intermediate point, which remained independent in the multivariate analysis. We also detected an additive effect of both polymorphisms in the multivariate analysis. High-affinity alleles may contribute to a quicker response owing to a more efficient removal of relevant cells expressing TNF.CONCLUSIONS AND RELEVANCE:Preliminary results of this pilot study on the pharmacogenetics of FcγR and biological therapy in psoriasis suggest a role with clinical implications for FcγRIIA-H131R and FcγRIIIA-V158F polymorphisms in the outcome of anti-TNF treatment of psoriasis. These results might help dermatologists in guiding therapeutic decisions, especially in very severe cases where a quick response is needed.

To the Editor: Bullous pemphigoid (BP) is caused by the deposition of IgG against BP180 antigen in the basement membrane zone. Topical or systemic corticosteroids generally control the disease, but severe cases require treatment with additional immunosuppressive agents. It is unclear which immunogenetic factors account for these different therapeutic outcomes. Fc gamma receptor IIb (FcγRIIB) is an inhibitory protein expressed on hematopoietic membrane cells, which interacts with the Fc portion of IgG. Coligation of FcγRIIB with the B-cell antigen receptor (BCR) mediates intracellular signals leading to the apoptosis and down-regulation of B-cells with a subsequent decrease in antibody production.1Chen J.Y. Wang C.M. Ma C.C. Luo S.F. Edberg J.C. Kimberly R.P. et al.Association of a transmembrane polymorphism of Fcgamma receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients.Arthritis Rheum. 2006; 54: 3908-3917Crossref PubMed Scopus (62) Google Scholar We report a case of severe BP that was homozygous for the defective allele of the FcγRIIB-Ile187Thr polymorphism. In September 2000, a 65-year-old woman presented with a generalized blistering eruption. She had a 2-year history of localized blisters that appeared when the dose of an oral corticosteroid she received for treatment of asthma was tapered. A skin biopsy specimen revealed a subepidermal blister with abundant eosinophils. Both direct and indirect immunofluorescence studies were diagnostic of BP. Treatment with prednisone 1 mg/kg/day was effective in healing the lesions, but when the dose was reduced, she suffered a severe flare. Very high titers of antibodies against the NC16A epitope of BP180 were detected (118 index value measured by enzyme-linked immunosorbent assay). The patient continued to develop new lesions despite taking prednisone (50 mg/day), azathioprine (150 mg/day), and doxycycline (200 mg/day). Between February and June 2001, she required three infusions of intravenous cyclophosphamide (1 g/m2) combined with daily oral cyclophosphamide (50 mg/day) and three cycles of plasma exchange to achieve disease control (Fig 1). Cyclophosphamide was discontinued and replaced with dapsone (50 mg/day) because of bone marrow toxicity. During the following 18 months, systemic corticosteroid therapy was slowly tapered and withdrawn, and anti-BP180 antibodies became undetectable. In March 2004, she presented with severe recurrent blistering that was controlled with oral prednisone. Since 2006, she has not required treatment. In the course of a research project on Fc gamma receptors, mutation analysis was performed to look for the FcγRIIB-Ile187Thr polymorphism. The patient was found to be homozygous for the minor allele -187Thr. Animal models have confirmed the importance of the inhibitory role of FcγRIIB in maintaining immune tolerance.2Tarasenko T. Dean J.A. Bolland S. Fc gamma RIIB as a modulator of autoimmune disease susceptibility.Autoimmunity. 2007; 40: 409-417Crossref PubMed Scopus (48) Google Scholar An analysis of four Asian populations strongly linked the -187Thr allele with systemic lupus erythematosus.1Chen J.Y. Wang C.M. Ma C.C. Luo S.F. Edberg J.C. Kimberly R.P. et al.Association of a transmembrane polymorphism of Fcgamma receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients.Arthritis Rheum. 2006; 54: 3908-3917Crossref PubMed Scopus (62) Google Scholar Li et al3Li X. Wu J. Carter R.H. Edberg J.C. Su K. Cooper G.S. et al.A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling.Arthritis Rheum. 2003; 48: 3242-3252Crossref PubMed Scopus (161) Google Scholar showed that the -187Thr variant is less effective than the -187Ile allele in inhibiting BCR-dependent activating signals in mouse B cells, which may determine an increase in autoantibody production in vivo. This defective function might be caused by an impaired recruitment of -187Thr to membrane lipid rafts (a prerequisite for the performance of its inhibitory functions).4Floto R.A. Clatworthy M.R. Heilbronn K.R. Rosner D.R. MacAry P.A. Rankin A. et al.Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts.Nat Med. 2005; 11: 1056-1058Crossref PubMed Scopus (265) Google Scholar The frequency of the -187Thr/Thr genotype in white populations is around 2%.5Magnusson V. Zunec R. Odeberg J. Sturfelt G. Truedsson L. Gunnarsson I. et al.Polymorphisms of the Fc gamma receptor type IIB gene are not associated with systemic lupus erythematosus in the Swedish population.Arthritis Rheum. 2004; 50: 1348-1350Crossref PubMed Scopus (40) Google Scholar Given the pivotal involvement of FcγRIIB in regulating the balance between tolerance and autoimmunity, the rarity of our patient's genotype, and her severe clinical course, we speculate that the FcγRIIB-Ile187Thr polymorphism may act as an immunogenetic modifier in BP. The severity (and chronicity) of this case could be partially explained by the presence of -187Thr receptor on B cells, leading to the increased, sustained, and unrepressed production of anti-BP180 antibodies.

To the Editor: Bullous pemphigoid (BP) is characterized by the deposition of complement and antibodies (Abs) against the hemidesmosomal protein BP180 on the basal membrane zone (BMZ). Neutrophils may play a central role through binding to the Fc portion of IgG anti-BP180 via Fc gamma receptors (FCGRs) and then secreting enzymes that digest the BMZ extracellular matrix.1Zhao M. Trimbeger M.E. Li N. Diaz L.A. Shapiro S.D. Liu Z. Role of FcRs in animal model of autoimmune bullous pemphigoid.J Immunol. 2006; 177: 3398-3405PubMed Google ScholarThe FCGR gene family codes activating (eg, FCGR2A and 3A) and inhibitory (FCGR2B) membrane receptors. Upon binding to the IgG Fc fragment, activating FCGRs mediate different immune functions (eg, degranulation of neutrophils or macrophage-mediated clearance of immunocomplexes), while FCGR2B downregulate these actions. Single-nucleotide polymorphisms (SNPs) affecting receptor affinity (and therefore cell functions) have been described.2Nimmerjahn F. Ravetch J.V. Fc-receptors as regulators of immunity.Adv Immunol. 2007; 96: 179-204Crossref PubMed Scopus (302) Google Scholar Clinical studies have associated these SNPs with autoimmune disorders (eg, systemic lupus erythematosus3Chen J.Y. Wang C.M. Ma C.C. Luo S.F. Edberg J.C. Kimberly R.P. et al.Association of a transmembrane polymorphism of Fcgamma receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients.Arthritis Rheum. 2006; 54: 3908-3917Crossref PubMed Scopus (60) Google Scholar).We hypothesized that the high affinity alleles of the activating FCGRs polymorphisms could lead to a greater degree of neutrophil activation, degranulation, and BMZ damage. FCGR2B-I187T polymorphism may also play a role by affecting the inhibition of neutrophil degranulation. The objective of this study was to investigate whether FCGR2A, FCGR3A, and FCGR2B polymorphisms are BP markers and/or disease modifiers.SNPs genotyping was performed in 115 blood donor controls and 41 white patients. BP diagnosis was made on the basis of typical clinical, histopathologic, and immunofluorescence features. We performed a retrospective review of patients' charts, and disease severity was assessed according to the therapy administered, with use (ever) of immunosuppressants considered to signify more severe disease than treatment with glucocorticoids (systemic, topic, or both) alone.The FCGR2A-H131R (H, high-affinity allele; R, low-affinity allele) and FCG2B-I187T (T, with a lower membrane expression) polymorphisms were assessed using a polymerase chain reaction sequencing–based typing method. A previously reported allele-specific polymerase chain reaction method4Leppers-van de Straat F.G. van der Pol W.L. Jansen M.D. Sugita N. Yoshie H. Kobayashi T. et al.A novel PCR-based method for direct Fc gamma receptor IIIa (CD16) allotyping.J Immunol Methods. 2000; 242: 127-132Crossref PubMed Scopus (61) Google Scholar was used to genotype the FCGR3A-V158F polymorphism (V, high-affinity allele; F, low-affinity allele; Fig 1).There were no differences in the distribution of genotypes, pooled genotypes, and allele frequencies between BP patients and controls (data not shown), which suggest that these polymorphisms are not markers of BP. However, in the only previously published study on FCGRs SNPs and BP, Weisenseel et al5Weisenseel P. Martin S. Partscht K. Messer G. Prinz J.C. Relevance of the low-affinity type of the Fcgamma-receptor IIIa-polymorphism in bullous pemphigoid.Arch Dermatol Res. 2007; 299: 163-164Crossref PubMed Scopus (16) Google Scholar found that the FCGR3A-158FF genotype was significantly enriched in BP. Because their study included 26 more patients, our results may have been influenced by a small sample size.We also investigated whether FCGRs polymorphisms influence disease severity using a multivariate logistic regression model. We detected a nearly significant (P = .06) association between the presence of the FCGR3A-158F allele and the use of immunosuppressants (Table I).Table IMultivariate logistic regression model of bullous pemphigoid severity according to the intensity of the therapy administeredUse (ever) of immunosuppressants vs glucocorticoids aloneExplanatory variableOR (95% CI)PFCGR2A (HR + RR vs HH)0.50 (0.06-4.49).54FCGR3A (VF + FF vs VV)7.41 (0.89-61.77).06FCGR2B (IT + TT vs II)0.51 (0.07-3.60).50Sex0.37 (0.08-1.64).19Age of onset0.97 (0.91-1.05).46Follow-up (mo)0.98 (0.95-1.01).22CI, Confidence interval; FCGR, Fc gamma receptors; OR, odds ratio.HH, HR, RR, VV, VF, and FF are genotypes. High/low affinity refers to alleles. “HR + RR” refers to those patients who presented the R allele (the low-affinity allele) in their genotype. Likewise “VF + FF” means presence of the low-affinity allele (the F allele of the FCGR3A-V158F polymorphism). Open table in a new tab Therefore, our initial hypothesis is challenged by both our results and those of Weisenseel et al,5Weisenseel P. Martin S. Partscht K. Messer G. Prinz J.C. Relevance of the low-affinity type of the Fcgamma-receptor IIIa-polymorphism in bullous pemphigoid.Arch Dermatol Res. 2007; 299: 163-164Crossref PubMed Scopus (16) Google Scholar in which the FCGR3A-158F low-affinity allele (and not the high-affinity one) is clinically associated with BP. The FCGR3A-158F allele may play a role in BP pathogenesis by reducing the macrophage-mediated clearance of anti-BP180 Abs. As a consequence, more pathogenic Abs may deposit at the site of inflammation, which in turn would enhance complement activation. It has been shown that membrane levels of activating FCGR are upregulated by C5a.6Shushakova N. Skokowa J. Schulman J. Baumann U. Zwirner J. Schmidt R.E. et al.C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex–induced lung disease.J Clin Invest. 2002; 110: 1823-1830Crossref PubMed Scopus (245) Google Scholar It is possible that the degree of neutrophil activation relies much more on the amount of FCGR3A membrane expression than on the polymorphism-dependent affinity. To the Editor: Bullous pemphigoid (BP) is characterized by the deposition of complement and antibodies (Abs) against the hemidesmosomal protein BP180 on the basal membrane zone (BMZ). Neutrophils may play a central role through binding to the Fc portion of IgG anti-BP180 via Fc gamma receptors (FCGRs) and then secreting enzymes that digest the BMZ extracellular matrix.1Zhao M. Trimbeger M.E. Li N. Diaz L.A. Shapiro S.D. Liu Z. Role of FcRs in animal model of autoimmune bullous pemphigoid.J Immunol. 2006; 177: 3398-3405PubMed Google Scholar The FCGR gene family codes activating (eg, FCGR2A and 3A) and inhibitory (FCGR2B) membrane receptors. Upon binding to the IgG Fc fragment, activating FCGRs mediate different immune functions (eg, degranulation of neutrophils or macrophage-mediated clearance of immunocomplexes), while FCGR2B downregulate these actions. Single-nucleotide polymorphisms (SNPs) affecting receptor affinity (and therefore cell functions) have been described.2Nimmerjahn F. Ravetch J.V. Fc-receptors as regulators of immunity.Adv Immunol. 2007; 96: 179-204Crossref PubMed Scopus (302) Google Scholar Clinical studies have associated these SNPs with autoimmune disorders (eg, systemic lupus erythematosus3Chen J.Y. Wang C.M. Ma C.C. Luo S.F. Edberg J.C. Kimberly R.P. et al.Association of a transmembrane polymorphism of Fcgamma receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients.Arthritis Rheum. 2006; 54: 3908-3917Crossref PubMed Scopus (60) Google Scholar). We hypothesized that the high affinity alleles of the activating FCGRs polymorphisms could lead to a greater degree of neutrophil activation, degranulation, and BMZ damage. FCGR2B-I187T polymorphism may also play a role by affecting the inhibition of neutrophil degranulation. The objective of this study was to investigate whether FCGR2A, FCGR3A, and FCGR2B polymorphisms are BP markers and/or disease modifiers. SNPs genotyping was performed in 115 blood donor controls and 41 white patients. BP diagnosis was made on the basis of typical clinical, histopathologic, and immunofluorescence features. We performed a retrospective review of patients' charts, and disease severity was assessed according to the therapy administered, with use (ever) of immunosuppressants considered to signify more severe disease than treatment with glucocorticoids (systemic, topic, or both) alone. The FCGR2A-H131R (H, high-affinity allele; R, low-affinity allele) and FCG2B-I187T (T, with a lower membrane expression) polymorphisms were assessed using a polymerase chain reaction sequencing–based typing method. A previously reported allele-specific polymerase chain reaction method4Leppers-van de Straat F.G. van der Pol W.L. Jansen M.D. Sugita N. Yoshie H. Kobayashi T. et al.A novel PCR-based method for direct Fc gamma receptor IIIa (CD16) allotyping.J Immunol Methods. 2000; 242: 127-132Crossref PubMed Scopus (61) Google Scholar was used to genotype the FCGR3A-V158F polymorphism (V, high-affinity allele; F, low-affinity allele; Fig 1). There were no differences in the distribution of genotypes, pooled genotypes, and allele frequencies between BP patients and controls (data not shown), which suggest that these polymorphisms are not markers of BP. However, in the only previously published study on FCGRs SNPs and BP, Weisenseel et al5Weisenseel P. Martin S. Partscht K. Messer G. Prinz J.C. Relevance of the low-affinity type of the Fcgamma-receptor IIIa-polymorphism in bullous pemphigoid.Arch Dermatol Res. 2007; 299: 163-164Crossref PubMed Scopus (16) Google Scholar found that the FCGR3A-158FF genotype was significantly enriched in BP. Because their study included 26 more patients, our results may have been influenced by a small sample size. We also investigated whether FCGRs polymorphisms influence disease severity using a multivariate logistic regression model. We detected a nearly significant (P = .06) association between the presence of the FCGR3A-158F allele and the use of immunosuppressants (Table I). CI, Confidence interval; FCGR, Fc gamma receptors; OR, odds ratio. HH, HR, RR, VV, VF, and FF are genotypes. High/low affinity refers to alleles. “HR + RR” refers to those patients who presented the R allele (the low-affinity allele) in their genotype. Likewise “VF + FF” means presence of the low-affinity allele (the F allele of the FCGR3A-V158F polymorphism). Therefore, our initial hypothesis is challenged by both our results and those of Weisenseel et al,5Weisenseel P. Martin S. Partscht K. Messer G. Prinz J.C. Relevance of the low-affinity type of the Fcgamma-receptor IIIa-polymorphism in bullous pemphigoid.Arch Dermatol Res. 2007; 299: 163-164Crossref PubMed Scopus (16) Google Scholar in which the FCGR3A-158F low-affinity allele (and not the high-affinity one) is clinically associated with BP. The FCGR3A-158F allele may play a role in BP pathogenesis by reducing the macrophage-mediated clearance of anti-BP180 Abs. As a consequence, more pathogenic Abs may deposit at the site of inflammation, which in turn would enhance complement activation. It has been shown that membrane levels of activating FCGR are upregulated by C5a.6Shushakova N. Skokowa J. Schulman J. Baumann U. Zwirner J. Schmidt R.E. et al.C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex–induced lung disease.J Clin Invest. 2002; 110: 1823-1830Crossref PubMed Scopus (245) Google Scholar It is possible that the degree of neutrophil activation relies much more on the amount of FCGR3A membrane expression than on the polymorphism-dependent affinity.

ABSTRACTGene polymorphisms, giving rise to low serum levels of mannose-binding lectin (MBL) or MBL-associated protease 2 (MASP2), have been associated with an increased risk of infections. The objective of this study was to assess the outcome of intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS) regarding the existence of functionally relevantMBL2andMASP2gene polymorphisms. The study included 243 ICU patients with SIRS admitted to our hospital, as well as 104 healthy control subjects.MBL2andMASP2single nucleotide polymorphisms were genotyped using a sequence-based typing technique. No differences were observed regarding the frequencies of low-MBL genotypes (O/O and XA/O) andMASP2polymorphisms between patients with SIRS and healthy controls. Interestingly, ICU patients with a noninfectious SIRS had a lower frequency for low-MBL genotypes and a higher frequency for high-MBL genotypes (A/A and A/XA) than either ICU patients with an infectious SIRS or healthy controls. The existence of low- or /high-MBL genotypes or aMASP2polymorphism had no impact on the mortality rates of the included patients. The presence of high-MBL-producing genotypes in patients with a noninfectious insult is a risk factor for SIRS and ICU admission.

Some deficient genetic polymorphisms of the innate immune system have been correlated to a higher susceptibility to different infections, especially in immunocompromised patients. The possible association between an increased incidence of pneumococcal bacteremia in HIV-infected patients, and deficient polymorphisms of the mannose-binding lectin (MBL), MBL-associated serine protease 2 (MASP-2), and toll-like receptors (TLR) 2 and 4 is analyzed by means of a case-control study. Cases: HIV-infected patients with pneumococcal bacteremia. Controls: HIV-infected patients without previous pneumococcal bacteremia matched with cases by sex and CD4 count in a 2:1 ratio. Fifty-seven cases and 114 controls were studied. Demographics, HIV infection status, antiretroviral therapy, risk factors for pneumococcal disease, and genotypes of MBL2, MASP2, TLR2 and TLR4 were analyzed. The prevalence of the MBL2, MASP2, TLR2 and TLR4 gene polymorphisms was similar in both groups. No statistical significance was found (OR 0.77, IC95% 0.27-2.13) when analyzing the possible association of MBL2 deficient polymorphisms with pneumococcal bacteremia. In HIV infected patients, no association between the presence of deficient polymorphisms of MBL2, MASP2, TLR2 and TLR4 and the incidence of pneumococcal bacteremia was found.

ABSTRACTStructural and promoterMBL2gene polymorphisms responsible for low MBL levels are associated with increased risk of infection. The objective of this study was to assess the possible association between polymorphisms of theMBL2gene and the incidence of septic shock and bacteremia in patients with acute pyelonephritis due toEscherichia coli. The study included 62 female patients with acute pyelonephritis due toE. coliwho required hospital admission, as well as 133 healthy control subjects. Six single-nucleotide polymorphisms (−550 G/C, −221 C/G, +4 C/T, codon 52 CGT/TGT, codon 54 GGC/GAC, and codon 57 GGA/GAA) in theMBL2gene were genotyped by using a sequence-based typing technique. No significant differences were observed in the frequencies for low-expressionMBL2genotypes (O/O and LXA/O) between patients with acute pyelonephritis and healthy controls. Patients with acute pyelonephritis and septic shock had a higher incidence of low-expressionMBL2genotypes than patients with acute pyelonephritis without septic shock (odds ratio = 9.019, 95% confidence interval = 1.23 to 65.93;P= 0.03). No association was found between bacteremic acute pyelonephritis and low-expressionMBL2genotypes. We found that low-expressionMBL2genotypes predispose to septic shock but not to bacteremia in patients withE. coli-induced acute pyelonephritis. Determination ofMBL2polymorphisms could be useful for assessing the risk of septic shock in women undergoing acute pyelonephritis.

BACKGROUND:Genetically defined deficiencies in key components of the innate immune system have been associated with a greater risk of infection. The aim of this study was to assess the influence of genetic variability of innate immune receptors (mannose-binding lectin [MBL], mannose-associated serine-protease-2 [MASP-2], and Toll-like receptors [TLR4]) in the risk of infections after a kidney transplantation.METHODS:All patients undergoing a kidney or kidney-pancreas transplantation during a 3-year period were included. Functionally relevant mutations in MBL2, MASP2, and TLR4 genes were determined by DNA sequencing. The incidence of major bacterial infections, asymptomatic cytomegalovirus (CMV) infection, and CMV disease were compared among groups.RESULTS:There were no differences regarding major transplant characteristics among groups. Older age, requirements for posttransplant hemodialysis, and pretransplant diabetes, but not gene polymorphisms, were associated with a greater number of bacterial infections. In univariate analysis, low-MBL genotypes were associated with CMV disease in pretransplant CMV seropositive patients (P=0.015), whereas the TLR4 mutation was associated with higher risk of CMV primary infection (P=0.024). TLR4 mutation was an independent factor associated with CMV disease (odds ratio 5.84, 95% confidence interval 1.35-25.20, P=0.018).CONCLUSION:Polymorphisms of innate immunity receptors, especially TLR4 mutation, were associated with higher risk of CMV disease, while susceptibility to other infectious disorders was not observed.