Immunogenetic Correlates Research Articles

CLINICAL-IMMUNOGENETIC RELATIONSHIP IN CHILDREN WITH CHRONIC TONSILLITIS AND ASSOCIATED DISEASES

General Background: Chronic tonsillitis is a prevalent condition in children, often linked to various immunogenetic factors that influence its pathogenesis and associated diseases. Specific Background: The role of HLA (Human Leukocyte Antigen) system A and B loci in chronic tonsillitis remains inadequately understood, particularly regarding their clinical significance and the immunogenetic correlations with related conditions. Knowledge Gap: While prior studies have examined the genetic factors associated with chronic tonsillitis, there is a lack of comprehensive research focusing on the specific HLA loci and their implications for clinical outcomes in affected children. Aims: This study aims to determine the indicators of HLA A and B loci in children with chronic tonsillitis and to explore the clinical-immunogenetic correlations with associated diseases. Results: The findings demonstrate significant associations between specific HLA alleles and the severity of chronic tonsillitis, highlighting potential immunogenetic predispositions that influence disease progression and comorbidities. Novelty: This research introduces a novel perspective by linking HLA system indicators directly to clinical outcomes, thereby providing new insights into the immunogenetic mechanisms underlying chronic tonsillitis in children. Implications: The identification of these immunogenetic factors could enhance the understanding of chronic tonsillitis pathophysiology and inform personalized treatment strategies, ultimately improving patient management and outcomes in pediatric populations.

Differential gene expression in relation to mating system in Peromyscine rodents.

Behaviors that increase an individual's exposure to pathogens are expected to have important effects on immunoactivity. Because sexual reproduction typically requires close contact among conspecifics, mating systems provide an ideal opportunity to study the immunogenetic correlates of behaviors with high versus low risks of pathogen exposure. Despite logical links between polygynandrous mating behavior, increased pathogen exposure, and greater immunoactivity, these relationships have seldom been examined in nonhuman vertebrates. To explore interactions among these variables in a different lineage of mammals, we used RNAseq to study the gene expression profiles of liver tissue—a highly immunoactive organ—from sympatric populations of the monogamous California mouse (Peromyscus californicus) and two polygynandrous congeners (P. maniculatus and P. boylii). Differential expression and co‐expression analyses revealed distinct patterns of gene activity among species, with much of this variation associated with differences in mating system. This tendency was particularly pronounced for MHC genes, with multiple MHC Class I genes being upregulated in the two polygynandrous species, as expected if exposure to sexually transmitted pathogens varies with mating system. Our results underscore the role of mating behavior in influencing patterns of gene expression and highlight the use of emerging transcriptomic tools in behavioral studies of free‐living animals.

Quantifying Ongoing HIV-1 Exposure in HIV-1–Serodiscordant Couples to Identify Individuals With Potential Host Resistance to HIV-1

Immunogenetic correlates of resistance to HIV-1 in HIV-1-exposed seronegative (HESN) individuals with consistently high exposure may inform HIV-1 prevention strategies. We developed a novel approach for quantifying HIV-1 exposure to identify individuals remaining HIV-1 uninfected despite persistent high exposure. We used longitudinal predictors of HIV-1 transmission in HIV-1 serodiscordant couples to score HIV-1 exposure and define HESN clusters with persistently high, low, and decreasing risk trajectories. The model was validated in an independent cohort of serodiscordant couples. We describe a statistical tool that can be applied to other HESN cohorts to identify individuals with high exposure to HIV-1. HIV-1 exposure was best quantified by frequency of unprotected sex with, plasma HIV-1 RNA levels among, and presence of genital ulcer disease among HIV-1-infected partners and by age, pregnancy status, herpes simplex virus 2 serostatus, and male circumcision status among HESN participants. Overall, 14% of HESN individuals persistently had high HIV-1 exposure and exhibited a declining incidence of HIV-1 infection over time. A minority of HESN individuals from HIV-1-discordant couples had persistent high HIV-1 exposure over time. Decreasing incidence of infection in this group suggests these individuals were selected for resistance to HIV-1 and may be most appropriate for identifying biological correlates of natural host resistance to HIV-1 infection.

Toll-like receptor gene variants associated with bacterial vaginosis among HIV-1 infected adolescents

Bacterial vaginosis (BV) is a common vaginal disorder in women of reproductive age, especially among women with HIV-1 infection. Several bacterial products including lipopolysaccharides (LPS), lipoteichoic acids (LTA), and peptidoglycans (PGN) are stimulatory ligands for Toll-like receptors (TLRs), and recent evidence indicates the important role of variation in TLR genes for permitting overgrowth of gram negative and BV-type flora. We assessed whether genetic polymorphisms in five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR9) could be determinants of differential host immune responses to BV in 159 HIV-1-positive African American adolescents enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) study. BV was assessed biannually and diagnosed either by a Nugent score of at least 7 of 10, or using the Amsel criteria. Cox-proportional hazards regression models, adjusted for concurrent Chlamydia and Gonorrhea infections, douching, and absolute CD4 cell count, were used to identify host genetic factors associated with BV. Two SNPs were associated with BV as diagnosed by the Nugent score and the combined criteria: a minor allele G of rs4986790 (frequency=0.07), which encodes a His to Tyr substitution in TLR4 (HR=1.47, 95% CI 1.15–1.87) and rs187084 (frequency=0.24) on TLR9. The minor allele of rs1898830 (frequency=0.13) was associated with an increased hazard of BV defined by the Amsel criteria (HR=1.86, 95% CI 1.17–2.95). Further studies are warranted to confirm the associations of TLR gene variants and also to understand the underlying pathways and immunogenetic correlates in the context of HIV-1 infection.

Immunogenetic correlates of Neisseria gonorrhoeae infection in adolescents.

Understanding host factors modulating immunity to Neisseria gonorrhoeae infection may benefit work on vaccine development. We analyzed longitudinal data collected from 485 male and female adolescents to determine genetic correlates of genital gonorrhea. Cytokine data from 388 females were analyzed to assess immunologic markers of gonorrhea and their relationship to genetic correlates. The T-G haplotype defining interleukin-2 (IL-2) gene promoter and intron 1 polymorphisms (-330T and -166G) was more frequently found in individuals who had gonorrhea (relative odds = 3.2, P = 0.01). Among 3 endocervical cytokines measured, IL-10 and IL-12 concentrations were higher and IL-2 lower when gonorrhea was detected. The decrease in endocervical IL-2 after gonorrhea acquisition was mostly restricted to subjects with the IL2 T-G haplotype, which may reflect involvement of a pathogen-specific and genetically mediated mechanism for differential IL-2 responses at genital mucosa. In addition, 2 human leukocyte antigen variants (Cw*04 and DQB1*05) were also independently associated with gonorrhea (adjusted relative odds = 1.9 and 0.5, respectively; P <0.05 for both). Confirmation of immunogenetic correlates of gonorrhea in larger cohorts may be useful in guiding further research on both innate and adaptive immune responses to N. gonorrhoeae.

Myositis‐specific and myositis‐associated antibodies in a series of eighty‐eight mediterranean patients with idiopathic inflammatory myopathy

To determine the prevalence of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) and their clinical and immunogenetic correlations in Mediterranean patients with idiopathic inflammatory myopathies. Sera from 88 patients were studied for MSAs and MAAs by RNA and protein immunoprecipitation. HLA typing was performed by sequence-specific primer- and sequence-specific oligonucleotide-polymerase chain reaction and serology. Statistical analyses were performed with Student's t-test and Fisher's exact test. Cumulative survival probabilities were estimated by the Kaplan-Meier method and Cox regression analysis. Twenty-eight patients (30%) had MSAs, most commonly antisynthetase antibodies (23.9%). Six patients (7.5%) had anti-Mi-2 antibodies. No anti-signal recognition particles were found. Arthritis, mechanic's hands, interstitial lung disease, and sicca syndrome were more prevalent in patients with antisynthetase antibodies. Dysphagia and the need for more treatment courses were more frequent in patients who were anti-Mi-2 positive. Forty-three patients (48%) had MAAs, 20 (22%) with anti-Ro 60 and 18 (20.4%) with anti-Ro 52. Ten patients (11.4%) were positive for anti-PM-Scl, 6 (6.8%) for anti-RNP, and 1 for anti-Ku antibodies. Patients with PM-Scl, RNP, or Ro antibodies were more often classified as having overlap syndrome. Immunogenetic studies found a significant association between HLA-DR3 and the presence of antisynthetase antibodies (P = 0.049), anti-PM-Scl antibodies (P = 0.017), and interstitial lung disease (P = 0.03). No statistically significant differences in mortality, survival, or clinical course were observed between patients positive for MSAs or MAAs and the remaining patients. These results are consistent with those from other published series, although some differences warrant consideration. Autoantibody studies may be useful for defining more homogeneous groups of patients with idiopathic inflammatory myopathies.

Clinical and immunogenetic correlates of abacavir hypersensitivity

A patch test (PT) may be useful in defining true abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.

Immunogenetic correlates for Chlamydia trachomatis–Associated tubal infertility

Objective To understand immunogenetic mechanisms of Chlamydia trachomatis infection and tubal scarring. Methods We measured and compared previously significant human leukocyte antigen (HLA) class II DQ alleles, their linked DRB genes, and polymorphisms in selected cytokine genes (tumor necrosis factor α-308 promoter; transforming growth factor β1-10 and -25 codons; interleukin 10-1082, -819, and -592 promoters; interleukin 6-174 promoter; and interferon γ+874 codon 1) among Kenyan women with confirmed tubal infertility with and without C trachomatis microimmunofluorescence antibody. Results Two class II alleles, HLA-DR1*1503 and DRB5*0101, were detected less commonly in C trachomatis microimmunofluorescence seropositive women than in C trachomatis microimmunofluorescence seronegative women with infertility (0% versus 20%; odds ratio [OR] 0.05; 95% confidence interval [CI] 0, 0.7, and 6% versus 26%; OR 0.2; 95% CI 0.02, 1.0, respectively). These alleles are commonly linked as a haplotype at the DRB locus. This finding could not be explained through linkage disequilibrium with the other studied HLA or cytokine genes. Conclusion These alleles may lead to an immunologically mediated mechanism of protection against C trachomatis infection and associated tubal damage, or alternatively increase risk for tubal scarring due to another cause.

Hyperprolactinaemia in patients with heart failure: clinical and immunogenetic correlations.

Prolactin represents a stimulatory link between the neuroendocrine and immune systems, but its involvement in the neurohumoral adaptations to heart failure (HF) has not been explored. We prospectively studied 55 patients (45 males, 10 females, age 48 +/- 7 years) with NYHA Class II/III HF due either to dilated cardiomyopathy (CMP) (n = 33) or ischemic heart disease (IHD) (n = 22). Serum prolactin levels were determined by radioimmunoassay, soluble interleukin-2 receptor (sIL-2R) levels by enzyme-linked immunoassay and HLA-DQ genotyping with PCR. Left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDd) were assessed echocardiographically. Hyperprolactinaemia (17.3 +/- 4 ng mL-1 [Group I] vs. 4.64 +/- 2 ng mL-1 [Group II], P < 0.01) was found in 14 patients (8 with IHD, 6 with CMP). The distribution of HLA-DQB1 alleles was compared in the two groups and showed a significant increase in the frequency of *0301 (86% in Group I vs. 45% in Group II, P < 0.05). Histidine at position 30 of the HLA-DQB1 gene was found in 22% of Group II but in none of Group I patients. Furthermore, there was an inverse correlation between the presence of histidine at position 30 and the levels of serum prolactin. Both sIL-2R levels, a marker of T-cell activation, and concanavalin A-stimulated lymphocyte proliferation were lower in Group I patients (561 +/- 106 vs. 804 +/- 109 pg mL-1 and 20.8 +/- 4 vs. 37.3 +/- 5 cpmX103 [3H] thymidine, respectively). LVEF was significantly higher (32 +/- 5%) and LVEDd smaller (62.0 +/- 6 mm) in Group I compared to Group II (25 +/- 4% and 68.0 +/- 5 mm, respectively, P < 0.01) patients. Hyperprolactinaemia presents in 25% of patients with HF and may reflect decreased activation of T-lymphocytes associated with relatively preserved LV systolic function which is under immune-genetic control at the HLA-DQ locus.

Fine Specificity of Anti‐Fibrillin‐1 Autoantibodies in Primary Pulmonary Hypertension Syndrome

Autoantibodies to fibrillin-1 (Fbn-1) have been found in systemic sclerosis (SSc), calcinosis, Raynaud's esophagael dysmotility, sclerodectyly, and telaengectasia (CREST) and mixed connective tissue disease (MCTD) diseases. The purpose of this study was to determine whether patients with primary pulmonary hypertension (PPH) and appetite-suppressant-associated PPH have anti-Fbn-1 autoantibodies. In addition we assessed the human leucocyte antigen (HLA) class II alleles (DRB1, 3, 4, 5 and DQB1) in these patients in order to determine whether the response is genetically restricted. The frequency of anti-Fbn-1 autoantibodies in patient groups was compared with that of a control group of 88 healthy patients, and HLA was correlated similarly with a group of 51 healthy subjects. Anti-Fbn-1 autoantibodies were found at high frequency in PPH: in 70 of 75 adults with PPH (93%), in 28 of 33 children with PPH (84.8) and in 12 of 18 (67%) patients with appetite-suppressant-associated PPH. Utilization of two Fbn-1 fusion proteins allowed us to determine the dominant determinant region, recognized by anti-Fbn-1 autoantibodies, which may be located on the N-terminal fragment of the Fbn-1 protein. No significant immunogenetic correlations were found when the PPH patient groups were compared with normal controls. This novel category of autoantibodies is found in diseases characterized by endothelial and extracellular matrix protein alterations and fibrosis.

Clinical, serologic, and immunogenetic features in Polish patients with idiopathic inflammatory myopathies.

To determine the clinical, serologic, and immunogenetic correlations in patients with idiopathic inflammatory myopathies (IIM), and to evaluate the useful grouping of some diseases for practical clinical purposes. Patients with IIM were categorized according to clinical presentation as compared with autoantibody specificity. Serum samples from 84 patients were screened for myositis-specific autoantibodies (MSAs) by indirect immunofluorescence and double immunodiffusion. All sera were also studied by protein A-assisted immunoprecipitation. Genomic DNA was isolated from peripheral blood mononuclear cells, and HLA-DQA1 and DRB1 alleles were determined. The patients were seen and followed up for many years in the same center. MSAs were present in 19% of patients. The most common MSAs were antisynthetases in 13% of patients (Jo-1 10.7%, PL-12 1.2%, and EJ 1.2%), associated with the antisynthetase syndrome. Anti-SRP was found in 1.2% of patients, associated with polymyositis, and anti-Mi-2 in 4.9%, found exclusively in patients with dermatomyositis. The most frequent MSA was PM-Scl in 23.8% of patients, associated with scleromyositis, and Ku was present in 9.6% of patients with overlap syndromes. The alleles that were found at a significantly increased frequency were HLA-DRB1*0301 (59.4%) and DQA1*0501 (71.6%), which are in linkage disequilibrium. DQA1*0501 was present in 85.7% of patients with antisynthetases, and in 100% of patients with PM-Scl and Ku. The HLA-DRB1*0301; DQA1*0501 haplotype was found to be significantly increased in this population overall and in those myositis patients with antisynthetase, anti-PM-Scl, and anti-Ku antibodies. The results of this study confirm that IIM are heterogeneous syndromes, but can be divided into more useful groups on the basis of clinical, serologic, and immunogenetic features.

Immunogenetic correlates of susceptibility to infection with Heligmosomoides polygyrus in outbred mice

Outbred MF1 mice were characterized with respect to their susceptibility to infection with Heligmosomoides polygyrus (Nematoda) on the basis of faecal egg counts after 8 weeks of repeated infection (50 larvae/week). Selective breeding for resistance and susceptibility was carried out over 3 generations. The H-2 type of a sample of the mice was determined, and antigen recognition assessed on the basis of Western blots against adult and larval H. polygyrus homogenate. The selective breeding programme yielded very strong evidence for the heritability of susceptibility to infection. The results were consistent with a model of single gene control with resistance dominant over susceptibility. The presence of the H-2k haplotype was significantly associated with susceptibility, as was the recognition of a 17 kDa antigen in blots against both larval and adult worm homogenate. The proportion of mice phenotypically susceptible to infection, the proportion bearing the H-2k haplotype, and the proportion recognizing the 17 kDa antigen, were all approximately 0.25.

Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations.

In a prospective open study 44 Israeli patients with rheumatoid arthritis were treated with weekly low dose methotrexate (MTX) for up to 36 months. Nine patients withdrew from the study: six because of side effects and three due to inefficacy. One patient died of septicaemia following septic arthritis. Significant improvement, graded by Ritchie articular index, grip strength, physician's global assessment, erythrocyte sedimentation rate (ESR), and platelet counts, was noticed in response to treatment. Seronegative patients had a better clinical response. Transient gastrointestinal symptoms were common and correlated with increases of serum aspartate transaminase (AST). HLA-DR1 and DR7 were significantly associated with increased serum AST concentrations.

Subacute cutaneous lupus erythematosus: Clinical, serologic, and immunogenetic studies of forty-nine patients seen in a nonreferral setting

Subacute cutaneous lupus erythematosus has been clearly recognized as a distinct cutaneous manifestation of lupus erythematosus. Two forms have been described, an annular erythema and a papulosquamous variant. Previous data have suggested that these patients have a high incidence of mild to moderate systemic disease, anti-Ro (SS-A) antibodies, and human lymphocyte antigen (HLA)-DR3, particularly the annular form. We studied forty-nine patients with subacute cutaneous lupus erythematosus seen in local private practices in our area. Lesions of chronic cutaneous lupus erythematosus were seen in 34.8% of our patients. Twenty-five patients (51%) fulfilled the American Rheumatism Association criteria for the classification of systemic lupus erythematosus, and renal disease was present in nine of these patients (including 3 with decreased function). Antibodies to Ro (SS-A) and/or La (SS-B) were present in only sixteen patients, and HLA-DR3 was found in only seventeen patients. Twenty-two patients had inactive cutaneous disease at follow-up. We concluded that our patient population with subacute cutaneous lupus erythematosus skin lesions is less distinctive than previous literature suggests. The serologic and immunogenetic correlates were not demonstrated. The full range of lupus erythematosus-related disease was seen, although most patients follow a benign course.