1141526807Expression of inducible microsomal prostaglandin E synthase in local endometriosis lesions

Objective:  Leukocytes arriving to choriodecidua during labor are capable to secrete cytokines and collagenases that may play a role in extracellular matrix degradation leading to the rupture of amniochorion. The aim of this work was to study the role of amniochorion in the active recruitment of leukocytes through production of specific chemokynes during labor.
Methods:  Amniochorion explants were obtained from women at term with spontaneous labor ( n  = 4) and subjected to cesarean section without labor ( n  = 4). Explant cultures were carried out during 24 hr and an homogenate including the culture media was made after this period. Cell free extracts were tested in Boyden chambers for chemotaxis using leukocytes from maternal blood obtained from women with ( n  = 2) and without labor ( n  = 2). Attracted cells were analyzed by flow cytometry for count and immunophenotype. Chemokynes were identified in the extracts using a commercial chemiarray.
Results:  All tested amniochorion extracts induced chemotaxis for leukocytes; however, those from labor tissues induced a higher chemotactic activity than the correspondent non-in-labor tissues ( P  = 0.003). Chemotactic effect was higher over leukocytes from labor women ( P  = 0.001). More than 80% of the attracted cells were polymorphonuclears in all cases. IL-8 was the main chemokyne found in all extracts; however its concentration was increased in extracts from labor.
Conclusions:  Fetal membranes induced chemotaxis for leukocytes and this condition is enhanced by the presence of labor. Amniochorion under active labor secretes IL-8 which induces a preferential chemotaxis for polymorphonuclears. Infiltration of these cells in choriodecidua during labor may play a role in the amniochorion degradation associated to rupture.     

92-kd type IV collagenase (matrix metalloproteinase-9) activity in human amniochorion increases with labor.

To determine whether specific collagenolytic enzymes are expressed in human fetal membranes with labor, we examined gelatinase activity in extracts of amniochorion by zymography. The 92-kd gelatinase (MMP-9) was barely detectable in extracts of fetal membranes before the onset of labor but was readily demonstrable in extracts prepared from membranes isolated from laboring women or membranes collected immediately after delivery. In contrast, the 72-kd gelatinase (MMP-2) was detectable in extracts from pre- and post-labor membranes. Ethylenediaminetetracetic acid and the tissue inhibitor of metalloproteinases, TIMP-1, inhibited the gelatinase activities detected by zymography, confirming that the enzymes are metalloproteinase. Assay of amniochorion gelatinase activity using a radiolabeled denatured collagen substrate revealed a more than twofold increase in activity comparing pre-labor with post-labor fetal membrane extracts. A function-blocking anti-MMP-9 monoclonal antibody inhibited pre-labor membrane gelatinase activity by approximately 11.5%, which was only slightly greater inhibition than observed with irrelevant monoclonal antibodies. However, post-labor membrane gelatinase activity was reduced by 53% by the function-blocking antibody, indicating that MMP-9 is a major contributor to the increased gelatinase activity extractable from post-labor membranes. Western blot analyses demonstrated increased MMP-9 protein in amniochorion extracts after onset of labor. MMP-9 protein and mRNA were co-localized in amnion epithelium, underlying macrophages and chorion laeve trophoblast and decidual cells after labor. We conclude that 1) MMP-9 activity and protein in human amniochorion increases with labor and 2) MMP-9 is expressed by amnion epithelium, macrophages and chorion laeve trophoblast and decidual cells. The increased expression of MMP-9 may result in degradation of the extracellular matrix of the fetal membranes and facilitate their rupture under both physiological and pathological conditions.     

A High Dose of Intravenous Immunoglobulin Increases CD94 Expression on Natural Killer Cells in Women with Recurrent Spontaneous Abortion

Problem  A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy.
Method of study  By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy ( n  = 8).
Results  Expression percentages of inhibitory CD94 on NK cells significantly ( P =  0.01) increased after the therapy (58.8 ± 21.4% versus 71.0 ± 17.6%).
Conclusion  Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.     

Effects of Peritoneal Fluid from Endometriosis Patients on Interferon-γ-Induced Protein-10 (CXCL10) and Interleukin-8 (CXCL8) Released by Neutrophils and CD4+ T Cells

Problem  Intraperitoneal immuno-inflammatory changes may be associated with the pathogenesis of endometriosis. We evaluated the effects of peritoneal fluid obtained from patients with endometriosis (ePF) on the release of interferon-γ-induced protein-10 (IP-10/CXCL10) and interleukin-8 (IL-8/CXCL8) by neutrophils, CD4⁺ T cells, and monocytes.
Method of study  Neutrophils, CD4⁺ T cells, and monocytes were cultured with ePF and the chemokine levels in the supernatants were then measured using enzyme-linked immunosorbent assay.
Results  The addition of ePF to cultures of CD4⁺ T cells led to a significant increase in the release of IP-10 when compared with control PF without endometriosis (cPF). There was a positive correlation between the levels of IL-8 and IP-10 in ePF ( R  = 0.89, P  =   0.041), but not between the levels of IP-10 and IL-8 released by neutrophils, CD4⁺ T cells, and monocytes. The levels of IP-10 in ePF were positively correlated with the release of IP-10 by ePF-treated neutrophils ( R  = 0.89, P  <   0.001), CD4⁺ T cells ( R  = 0.93, P  <   0.001), and monocytes ( R  = 0.70, P  =   0.01). Moreover, the addition of ePF significantly enhanced the interferon-γ-induced release of IP-10 by nuetrophils and CD4⁺ T cells.
Conclusion  These findings suggest that neutrophils and T cells release differential levels of IP-10 and IL-8 in response to stimulation with ePF, and that these cells are a major source of IP-10 in the PF of endometriosis patients.     

Sputum neurokinin A in Egyptian asthmatic children and adolescents: relation to exacerbation severity

Background:  Neurogenic inflammation may participate in the development and progression of bronchial asthma. The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as neurokinin A (NKA) and substance P. Tachykinins are secreted from sensory airway nerves and inflammatory cells after allergens exposure. In clinical practice, assessment of airway inflammation is difficult. Therefore, detection of biological markers of airway inflammation in sputum might offer help for proper monitoring of asthma severity.
Aim of the study:  We aimed to measure sputum NKA in relation to acute asthma exacerbations of varying severity.
Methods:  Sputum NKA was measured by enzyme-linked immunosorbent assay in 24 children and adolescents during and after acute asthma exacerbation and 24 healthy matched controls.
Results:  Sputum NKA was significantly higher in asthmatic patients during acute exacerbation than controls [217.5 (284) vs 10 (7) ng/ml, P  < 0.001]. When patients with acute asthma exacerbation were followed-up till remission, sputum NKA levels decreased significantly, but they remained significantly higher than controls. Sputum NKA levels were significantly higher in severe than moderate and in moderate than mild exacerbations, and was negatively correlated to peak expiratory flow rate ( r  = −0.9, P  < 0.001). Sputum NKA had significant positive correlations to eosinophil counts in blood and sputum ( r  = 0.6, P  < 0.001 and r  = 0.7, P  < 0.001 respectively).
Conclusions:  Sputum NKA is up-regulated during acute asthma exacerbation and it positively correlates to its severity. Thus, NKA may aid in objective classification of the exacerbation severity. In addition, NKA may be a target for new asthma therapy.     

Expression of small breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast cancers

Aims:  Small breast epithelial mucin (SBEM) is a recently described gene product that shows promise as a new breast biomarker. The aim was to investigate for the first time SBEM protein expression in a large cohort ( n  = 300) of invasive breast cancers, its relationship to established clinical variables and its association with clinical outcome.
Methods and results:  Immunohistochemical analysis was performed on tissue microarrays consisting of 149 oestrogen receptor (ER) α− and 151 ERα+ breast cancers. Overall, 18% of tumours were SBEM+ ( n  = 53/300). However, SBEM protein was more frequently observed in ER− (22%) than in ER+ cancers (13%; P = 0.049). A significant association with psoriasin/S100A7 expression ( P  ≤ 0.0001) was observed in the entire cohort. SBEM was also positively associated with HER-2 ( P  = 0.046) in ER− cancers, and increased levels of SBEM were strongly associated with higher tumour grade ( P  = 0.0015). Furthermore, SBEM expression showed a trend towards an association with reduced overall survival and relapse-free survival in the ER+ cohort ( P  = 0.063 and P  = 0.072, respectively).
Conclusions:  Our results suggest that SBEM may identify a unique subset of breast cancers with poor prognosis and may have future implications for therapeutic management of this disease.     

1141355494Cytokine, chemokines and integrin levels in the severely preterm placenta distinguish between preeclampsia and other preinatal complications

Using a multiplex protein array, we tested the hypothesis that the concentrations of inflammatory proteins within placental chorionic stroma differ by perinatal complication. The chorionic plates of 30 singleton placentas were biopsied immediately after delivery for severe preeclampsia (PE), membrane rupture (pPROM) or preterm labor (PL) between 23–28 weeks and flash frozen after the amnion was removed. After thawing and homogenization, concentrations of select proteins were measured on the MesoScale Discovery platform. Analytes were grouped by the functional categories of: inflammation (IL1β, IL6, TNFα, IL18,), chemotaxis (IL8), endothelial effectors (P- and E-selectin, VCAM1, ICAM1, ICAM3, VEGF) and inflammatory modulation (IL10, TGFβ, IL1ra, thrombomodulin). ANOVA and K-means clustering examined differences between delivery indications. K-means clustering distinguished PE placentas from the others, but did not discriminate PL from pPROM. Both PL and pPROM had distinct subsets of placentas with either increased inflammatory or increased modulatory activity. PE placentas tended to have low concentrations of one inflammation indicator (IL-18 P  = 0.04), two endothelial effectors (E-selectin P  = 0.02; ICAM1 P  = 0.03), and one inflammation modulator (IL1ra P  = 0.01). On the other hand, PE placentas also had elevated levels of 2 inflammation modulators (TGFβ P  = 0.04; thrombomodulin P <  0.001) and elevated levels of one endothelial effector (VEGF P <  0.001). The placental inflammatory response differs by perinatal complication. The PE response has limited inflammatory activation and elevated VEGF levels. The PL and pPROM placentas appeared similar in their distribution of subgroups with inflammatory or modulatory responses. This suggests possible common pathologic antecedents and progression.     

Glutamate-L-cysteine ligase in breast carcinomas

Aims : To investigate the immunohistochemical expression of the catalytic and regulatory subunits of γ-glutamyl cysteine synthetase, i.e. glutamate-L-cysteine ligase (GLCL) in 274 invasive and in-situ breast carcinomas. GLCL is the rate-limiting enzyme in glutathione synthesis, which is one of the most important intracellular antioxidants participating in the detoxification reactions of several cytotoxic drugs.
Methods and results : In the tumour cells GLCL reactivity was observed in 50% and 44% of the cases for the catalytic and the regulatory subunits, respectively. There was a statistically significant association between their expression ( P =  0.002). Lobular invasive carcinomas expressed the catalytic and regulatory subunits more often than other tumours ( P =  0.050 and P  = 0.046, respectively). Also in-situ carcinomas expressed the catalytic subunit more often ( P = 0.005). Tumours showing no immunoreactivity for the catalytic subunit had axillary metastases significantly more often ( P =  0.013). Patients with tumours showing positivity for either subunit or both had a better survival ( P =  0.037). No difference in survival could be observed between GCLC-positive or -negative cases in the subgroup receiving chemotherapy.
Conclusions : Expression of the catalytic and regulatory subunits of GLCL is found in a substantial number of breast carcinomas and their expression is more pronounced in lobular invasive and in-situ carcinomas. Even though the overall expression of GLCL was associated with improved survival, no such effect was observed separately in the group receiving chemotherapy.     

Efficacy of desloratadine in intermittent allergic rhinitis: a GA2LEN study

Background:  The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines proposed a classification for allergic rhinitis based on the duration of symptoms (intermittent, persistent) rather than on the time of allergen exposure (seasonal, perennial). There is no placebo-controlled, randomized clinical trial on intermittent allergic rhinitis (IAR) to date. Desloratadine (DL) is recommended for the first-line treatment of seasonal and perennial allergic rhinitis.
Objectives:  To assess the efficacy and safety of DL in subjects with IAR based on the ARIA classification.
Methods:  Patients over 12 years of age with IAR were assessed over 15 days of treatment with DL 5 mg once daily ( n  = 276) or placebo ( n  = 271). The primary endpoint was the AM/PM reflective total 5 symptom score (T5SS). Secondary endpoints included AM/PM instantaneous T5SS and individual symptoms, therapeutic response, symptom severity by visual analogue scale, and quality-of-life.
Results:  The mean reduction of AM/PM reflective T5SS was significantly greater with DL than with placebo over 15 days (−3.01 vs −2.13, P  < 0.001) and on each individual day ( P  < 0.05). Mean AM instantaneous T5SS was reduced significantly with DL compared to placebo as early as day 2 (−1.84 vs −0.89; P  < 0.001). The therapeutic response and improvement in quality-of-life were significantly greater with DL than with placebo ( P  < 0.001 for each). The frequency of treatment-related adverse events was low and similar between DL (7.2%) and placebo (7.0%).
Conclusions:  This is the first large trial to show that treatment can be effective in IAR. Desloratadine was effective and safe.     

Functional Changes of Human Peripheral B-Lymphocytes in Pre-Eclampsia

Problem  The aim of our study was to investigate the functional changes of human peripheral B-lymphocytes in healthy and pre-eclamptic pregnancies.
Method of study  Twenty patients with pre-eclampsia and 15 healthy third-trimester pregnant women were recruited in this study. Peripheral blood mononuclear cells (PBMCs) were isolated and directly stained with fluorescein isothiocyanate (FITC)-labeled anti-CD27 monoclonal antibody (mAb) and phycoerythrin (PE)-labeled anti-CD38 mAb. The percentages of the individual B-cell subsets were estimated out of total lymphocytes by flow cytometric analysis. Additionally, the enriched PBMCs were cultured with or without the stimulation of pokeweed mitogen (PWM) for 5 days. Then morphologic observation of plasma cells was analysed by Wright-Giemsa stain, and antibody-producing cells were detected by enzyme-linked immunospot assay.
Results  The percentage of CD27⁻CD38⁻ naïve B-cells and CD27⁻CD38⁺ plasma cells did not differ between study groups ( P  >   0.05). The percentage of CD27⁺CD38⁻ memory B-cells and CD27⁺CD38⁺ plasma cell pre-cursors increased in pre-eclamptic women compared with the controls ( P  <   0.05). Irrespective of whether the PBMCs were stimulated with or w/o PWM in vitro , the mean percentages of generated plasma cells were significantly higher in pre-eclamptic group than in the controls ( P  <   0.05). There were more antibody-producing cells in pre-eclamptic women following the activation of PWM than those in the controls ( P <  0.01).
Conclusion  Our findings implicate that the functional changes of human circulating B-cells might contribute to the etiology of pre-eclampsia.     

Association and interaction analyses of eight genes under asthma linkage peaks

Background:  Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits.
Methods:  Ninety-five single nucleotide polymorphisms (SNP) located in eight genes ( CD28 , CTLA4 , ICOS , ADAM23 , ADAMTSL1 , MS4A2 , CDH26 and HRH3 ) were genotyped in >5000 individuals from Australian ( n  = 1162), Dutch ( n  = 99) and Danish ( n  = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene-wide thresholds for significance determined through simulation. Gene-by-gene and gene-by-environment analyses were also performed.
Results:  There was no overall evidence for association with seven of the eight genes tested when considering all genetic variation assayed in each gene. The exception was MS4A2 on chromosome 11q13, which showed weak evidence for association with IgE (gene-wide P  <   0.05, rs502581). There were no significant gene-by-gene or gene-by-environment interaction effects after accounting for the number of tests performed.
Conclusions:  The individual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak effect of MS4A2 polymorphisms on the variation of total IgE levels.     

Induced sputum and bronchial mucosal expression of interleukin-13 is not increased in chronic obstructive pulmonary disease

Background:  The Th2 cytokine interleukin-13 (IL-13) has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We sought to examine IL-13 expression in COPD subjects in induced sputum and bronchus specimens. We hypothesized that inflammatory cells expressing IL-13 localize to the airway smooth muscle bundle and bronchial glands.
Methods:  Interleukin-13 was measured in sputum samples from subjects with COPD ( n  = 34) across a range of severity (Global initiative for chronic Obstructive Lung Disease 2–4) and controls ( n  = 14) using ELISA. IL-13+ cells and inflammatory cells were enumerated within surgically resected proximal airway using immunohistochemical techniques from subjects with COPD ( n  = 10), smoking ( n  = 10) and nonsmoking controls ( n  = 8).
Results:  Sputum IL-13 was measurable in only 6/34 subjects with COPD and was not found in the smoking or nonsmoking control subjects. In subjects with COPD and controls there was a paucity of IL-13+ cells. The distribution of inflammatory cells within different airway compartments was similar in COPD and controls except for an increase in CD3⁺ lymphocytes within bronchial glands in COPD ( P  = 0.04).
Conclusions:  Our findings do not support a role for IL-13 in COPD. However, the tissue localization of inflammatory cells to airway compartments, particularly the increase of T cells in glands in COPD may be important in disease.     

Predictors of bronchial hyperresponsiveness in chronic rhinosinusitis with nasal polyp

Background:  Chronic rhinosinusitis with nasal polyposis (CRSNP) and asthma are inflammatory lesions of the respiratory epithelium. This study was conducted to evaluate predictive factors of bronchial hyperresponsiveness (BHR) in patients with CRSNP.
Methods:  BHR was evaluated using a methacholine bronchoprovocation test (MBPT) in 122 consecutive patients newly diagnosed with CRSNP at Seoul National University Hospital from January 2004 to June 2006. The following parameters were analyzed and compared between the BHR and non-BHR groups: symptoms, atopic status, current smoking, disease severity of CRSNP based on the Lund–Mackay scoring system of sinus CT, and counts of eosinophils in the serum and nasal tissues.
Results:  Thirty-five percent of the patients were found to have BHR, and BHR was found to occur more frequently in patients that were currently suffering from sneezing ( P  = 0.007). In addition, the mean eosinophil counts of the serum and nasal tissues were higher in the BHR group than in the non-BHR group ( P  = 0.001 for the serum, P  = 0.045 for the nasal tissues), and the eosinophil counts of the serum correlated to those of the nasal tissues ( r  = 0.334, P  = 0.013). The disease severity, as determined by the Lund–Mackay scoring system, was not different between the two groups ( P  > 0.05). The best cutoff serum eosinophil count for predicting BHR in CRSNP patients was determined to be 300 cells/μl (sensitivity 70%, specificity 70%).
Conclusion:  Taken together, these results indicate that moderate to severe sneezing and a serum eosinophil count ≥ 300 cells/μl may be predictive factors for BHR in patients with CRSNP.     

Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults

Background:  Filaggrin ( FLG ) null mutations are important genetic predisposing factors for atopic asthma and have recently been shown to influence controller and reliever medication needs in asthmatic children. Our objective was to study the role of FLG null alleles in asthma exacerbations.
Methods:  FLG mutations R501X and 2282del4 were assayed in 1135 individuals ranging from 3 to 22 years old with asthma from Tayside and Dumfries, Scotland. Asthma exacerbations over the previous 6 months were also studied.
Results:  The FLG mutations were significantly associated with greater risk of exacerbations in children with asthma. Exacerbations were significant for the R501X but not the 2282del4 mutation and the combined genotype compared to the wild-type with odds ratios of 1.97 (95% CI, 1.19–3.22; P  = 0.009) and 1.61 (95% CI, 1.08–2.40; P  = 0.021), respectively. Individuals with FLG null alleles were more likely to require oral steroids (31.4% vs 19.5%; OR = 1.89; P  =   0.021) for their exacerbations. There was also a 1.71-fold increased risk (42.6% vs 30%; P  =   0.041) of school absence owing to asthma exacerbations in asthmatic individuals with FLG null mutation. On sub-group analysis, the effect of FLG mutations on asthma exacerbations is significant ( P  =   0.045) only for participants with relatively mild asthma controlled on inhaled steroids, with inhaled albuterol according to need.
Conclusion:  In addition to their effect on asthma medication requirements reported previously, there is an association between the presence of FLG null mutations and the risk of asthma exacerbations in asthmatic children and young adults.     

Distribution of immunocompetent cells in decidua of controlled and uncontrolled (choriocarcinoma/hydatidiform mole) trophoblast invasion

Problem:  Pregnancy has been considered as a model of successfully controlled tissue invasion where trophoblast cells infiltrate the maternal decidua without being rejected or without destroying the tissue. In choriocarcinoma (CC) and hydatidiform mole (HM), a dysregulation of invasive (malignant/benign) trophoblast cells is present. Immunocompetent cells (IC) are known to be involved in rejection pathways of malignant cells and can also be identified in early pregnancy decidua. The aim of the present study was to identify the phenotype of IC in decidua of women with normal pregnancy (NP), CC and HM.
Methods:  Immunocompetent cells were detected by immunohistochemistry in decidual tissue from first trimester NP ( n  = 10), CC ( n  = 12) and HM ( n  = 11) using antibodies against CD8⁺, CD3⁺, CD56⁺, CD68⁺ cell surface markers and mast cell tryptase (MCT). A scaled eye piece was used for cell counting to obtain semiquantitative results. Statistical analysis was performed using Wilcoxon rank/Mann–Whitney tests.
Results:  We observed a significantly increased number of lymphocytes positive for CD8, CD3 and MCT positive granulocytes in CC and HM compared with the samples from NP (all P  ≤ 0.001). Lymphocytes positive for natural killer (NK) cell marker CD56 were significantly decreased in CC and HM versus NP ( P  ≤ 0.001). The number of CD68 positive cells (macrophages) were not significantly different among the tissue pools.
Conclusion:  The increase of CD8/CD3 T cells and mast cells in CC and HM and the decrease of CD56 cells, compared with NP, suggests the necessity of a balance between T and NK cells in controlling trophoblast invasion.     

Vacuum-assisted delivery is associated with late-onset asthma

Background:  Perinatal factors during delivery might modulate fetal immunological development and thereby be associated with the development of allergic diseases and asthma later.
Methods:  Perinatal data was recorded during pregnancy and at the time of delivery in regard to 5823 children who were born in Northern Finland in 1985–1986. Data from self-administered questionnaires were available at the ages of 7 and 15–16 years and skin prick tests for four main allergens were carried out at the age of 15–16 years. Only singletons delivered by the vaginal route were analyzed.
Results:  There was a higher prevalence of doctor-diagnosed asthma at any time of life among children who were delivered by vacuum extraction (RR 1.80, 95% CI 1.27–2.56; P  < 0.001) in comparison with spontaneously delivered children. In particular, this risk was increased as regards late-onset asthma (RR 2.41, 95% CI 1.52–3.81; P  < 0.001). Perinatal effects had less impact on the development of other asthma, atopy or hay fever.
Conclusions:  The delivery by vacuum extraction had significant impact on the development of late-onset asthma compared with spontaneously delivered children.     

Activating Killer Cell Immunoglobulin-Like Receptor Genes' Association with Recurrent Miscarriage

Problem  Natural killer (NK) cells are regulated through NK cell receptors such as killer cell immunoglobulin-like receptors (KIRs). KIRs are suspected of being involved in the causes of recurrent miscarriage (RM) as a higher proportion of activated NK cells were observed in women with RM when compared with that in controls. The aim of this study was to investigate if KIR genes coding for receptors known to have as ligands HLA class I molecules are correlated with RM.
Method of study  A matched case–control study was carried out in 68 south Brazilian Caucasian patient couples with RM and 68 control fertile couples. KIR genes were typed by PCR-Reverse SSO method.
Results The rate of possession of an elevated number of activating KIR genes (positive for five or six activating KIR genes out of six different activating KIR genes analyzed) in RM patient women was significantly higher ( P  =   0.0201) when compared with that in control fertile women. These data suggest that women carrying a high content of activating KIR genes have about threefold increased probability to develop RM [OR = 2.71; 95% CI (1.23–6.01)].
Conclusion  Our results indicate that RM could be associated with NK cell activation mediated by a profile rich in activating KIR genes.