Interleukin-6-174 G/C promoter polymorphism is associated with persistence of Chlamydia pneumoniae antibodies in young men.

A promoter polymorphism -174 G/C in the inflammatory cytokine interleukin-6 (IL-6) gene has been associated with differences in serum IL-6 levels and a risk for inflammatory conditions, such as cardiovascular diseases. We investigated whether this polymorphism is associated with Chlamydia pneumoniae, a common causative agent of respiratory infection with tendency for persistent infections, in 867 Finnish military recruits. IgG seropositivity in arrival and departure serum samples during 6-12 months of military service was considered as persistence of antibodies and a possible prolonged or chronic infection. The -174C allele was significantly associated with IgG seropositivity (P = 0.0002) and the persistence of IgG antibodies (P = 0.0002) as well as with slightly elevated C-reactive protein (CRP) levels (P = 0.003). In addition, the association was stronger when persistent C. pneumoniae antibodies were present together with elevated CRP than when either of them was positive alone (OR; 95% CI: 3.45; 2.00-5.98 and 1.41; 1.00-1.99, respectively). Our data suggest that IL-6 -174 G/C polymorphism is associated with persistence of C. pneumoniae antibodies and may be linked to the chronic or prolonged infection with systemic low-grade inflammation.

Chlamydia pneumoniae infection is associated with elevated body mass index in young men.

Chlamydia pneumoniae infection is said to be associated with obesity. We studied the association between C. pneumoniae infection and inflammation and increased BMI in 891 Finnish military recruits. IgG seropositivity in arrival and departure serum samples during 6-12 months of military service was considered as persistence of antibodies and a possible indication of chronic infection. Persistently high C-reactive protein (CRP) level (elevated on arrival and departure) (OR 2.2, 95% CI 1.3-3.9), and persistent C. pneumoniae antibodies (OR 2.1, 95% CI 1.5-2.8) were significant risk factors for overweight (BMI 25 kg/m2). In addition, those who had persistent antibodies and persistently elevated CRP levels, or those who had either of them, had a significantly higher BMI (kg/m2) compared to those who had neither of them (25.8 vs. 24.6 vs. 23.5, respectively; P<0.001). These results provide new information about the association between possible chronic C. pneumoniae infection and obesity in young men.

Effects of CD14, TLR2, TLR4, LPB, and IL-6 gene polymorphisms on Chlamydia pneumoniae growth in human macrophages in vitro.

Chlamydia pneumoniae is an obligate intracellular gram-negative bacterium, which causes respiratory infections in humans. It can infect various cell types, e.g. vascular endothelial cells, smooth muscle cells and monocyte-derived macrophages in vitro. The susceptibility of macrophages from healthy individuals to C. pneumoniae infection is highly variable. In this study, we evaluated the effects of innate immunity genes CD14 -260 C>T, TLR2 Arg753Gln, TLR4 Asp299Gly, LBP Phe436Leu and IL6 -174 G>C polymorphisms on C. pneumoniae growth in human macrophages in vitro. The growth of C. pneumoniae was highest in CD14 -260 C>T TT genotype cells and the difference to CC and CT genotypes was statistically significant (P = 0.032 and 0.022 respectively). The G-allele of the IL6 -174 G>C polymorphism had a positive influence on chlamydial growth; the difference was statistically significant only between CC and GC genotypes (P = 0.018). TLR2 Arg 753Gln, TLR4 Asp299Gly, LBP Phe436Leu polymorphisms showed no effect on chlamydial growth.

Susceptibility of human monocyte-macrophages to Chlamydia pneumoniae infection in vitro is highly variable and associated with levels of soluble CD14 and C. pneumoniae IgA and human HSP-IgG antibodies in serum.

Chlamydia pneumoniae, an intracellular microbe, causes respiratory infections and may participate in the development of atherosclerosis. It is able to survive and multiply in macrophages. The susceptibility of monocyte-macrophages from healthy individuals to C. pneumoniae infection in vitro was studied. Intracellular growth of C. pneumoniae, as an indicator of susceptibility to infection, was compared to serum levels of C-reactive protein, soluble CD14 (sCD14), human heat shock protein (HSP)-IgG, human HSP-IgA, C. pneumoniae IgG and IgA antibodies. The production of C. pneumoniae in infected macrophages was highly variable, ranging from 0 to 638 chlamydial genomes per human genome. Chlamydia pneumoniae production associated positively with serum C. pneumoniae IgA (titre: > or =10) and hHSP-IgG and negatively with sCD14 concentration. The association between sCD14 concentration, C. pneumoniae IgA and human HSP-IgG antibodies and C. pneumoniae production was statistically significant only among males. Age and gender did not correlate with the production. We hypothesize that persons whose macrophages cannot restrict the growth of C. pneumoniae are more prone to chronic infection by this agent.

Acute Chlamydia pneumoniae infections in asthmatic and non-asthmatic military conscripts during a non-epidemic period.

Chlamydia pneumoniae respiratory tract infections were studied in 512 male military conscripts (123 asthmatic and 389 non-asthmatic) taking part in 180-day service between July 2004 and July 2005 in Kajaani, Finland. Respiratory tract infections requiring a medical consultation were analysed prospectively. At baseline, at end of service, and during each episode of respiratory infection, blood samples were obtained for measurement of C. pneumoniae antibodies. Data concerning the clinical features of each infection episode were collected. Serological evidence of acute C. pneumoniae infection was found in 34 of the 512 conscripts with antibody data available, including 9.8% of the asthmatic subjects and 5.7% of the non-asthmatic subjects (p 0.111). A serological diagnosis could be made for 25 clinical episodes in 24 conscripts. The spectrum of respiratory tract infections included 13 episodes of mild upper respiratory tract infection and seven episodes of sinusitis, with five episodes involving asthma exacerbation. Two of three pneumonias were primary infections. Primary infections were diagnosed in five subjects, and re-infection/reactivation in 19 subjects, with the latter comprising 12 non-asthmatic subjects and seven asthmatic subjects (p 0.180). Prolonged infections were present in six asthmatic subjects and one non-asthmatic subject (p 0.001). A wide variety of respiratory tract infections, ranging from common cold to pneumonia, were associated with serologically confirmed C. pneumoniae infections. Infections were often mild, with common cold and sinusitis being the most common manifestations. Acute, rapidly resolved C. pneumoniae infections were equally common among asthmatic subjects and non-asthmatic subjects, whereas prolonged infections were more common among subjects with asthma.

Atopy and depression: results from the Northern Finland 1966 Birth Cohort Study.

Several studies have suggested an association between IgE-mediated atopic allergies and depression. The present study extends our understanding about putative gender differences of this association and provides further epidemiological evidence for our previous finding that the association between atopy and depression may be characteristic for females only. In order to clearly determine the presence of atopic disorders and depression, we used more valid tools than had been employed earlier and we had access to a database (the Northern Finland 1966 Birth Cohort), in which individuals were followed up prospectively until the age of 31 years. The information on allergic symptoms, verified by skin-prick tests and comprising data of 5518 individuals, was used to ascertain the presence of atopy. Depression was assessed with the help of Hopkins' Symptom Checklist-25 and self-reported doctor-diagnosed depression. After adjusting for a father's social class, mother's parity, and place of residence, logistic regression analyses showed that the risk of developing depression increased in parallel with the increasing severity of depression and, when compared with nonatopic subjects, was 3.0 to 4.7-fold up in atopic females and statistically significant. In atopic males, the association between atopy and depression was statistically significant only in the highest depression scores, the odds ratio being 6.3-fold. The results indicate that females suffering from atopic diseases might possess an elevated risk of developing depression already during early adulthood. In males, the association between these two disorders is evident only among the most severe manifestations of depression. Possible background theories, that is, genetic abnormalities in serotonin metabolism, HPA-axis dysfunction, and histamine theory are discussed.

Use of recombinant human granulocyte-colony stimulating factor in colorectal surgery.

The purpose of the current study was to assess the effects and safety of administering perioperative recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF, Filgrastim; Roche, Switzerland) to patients undergoing elective colorectal surgery. Thirty consecutive patients were prospectively randomized to receive either r-metHuG-CSF or placebo. Treatment with r-metHuG-CSF induced transient leukocytosis with shift to the left. The phagocytic or killing capacities of neutrophils were not altered in the patients treated with r-metHuG-CSF, but there was a decline in neutrophil chemotaxis. There were no serious adverse events associated with r-metHuG-CSF treatment. Thus, perioperative r-metHuG-CSF is safe for patients undergoing colorectal surgery. The presence of an increased number of functioning neutrophils may offer advantages in combating imminent infection.

HLA-DQA1 alleles and the presence of Helicobacter pylori antibodies.

Recent reports suggest that the HLA-DQA1 gene may be important in determining susceptibility to and outcome of Helicobacter pylori infection. To determine if there is an association between HLA-DQA1 alleles and H. pylori antibodies, DQA1 alleles and H. pylori-specific antibodies were determined in 199 random subjects of Finnish origin (mean age 43 years, range 22-69 years). H. pylori-specific class IgG antibodies were measured using the EIA method (Pyloriset-EIA-G, Orion Diagnostica, Espoo, Finland). HLA-DQA1 typing was carried out using PCR-SSP (PCR with sequence-specific primers). There were 64 subjects with H. pylori-specific class IgG antibodies (ab+) and 135 subjects without H. pylori-specific class IgG antibodies (ab-). Gene and phenotype frequencies of HLA-DQA1 alleles were similar in the ab+ and ab- subjects (P = NS). The data suggest that no single HLA-DQA1 allele is associated with the presence of serum antibodies against H. pylori.

Restricted and individual usage of T-cell receptor beta-gene variables in nickel-induced CD4+ and CD8+ cells.

Nickel allergy is manifested as contact allergic eczema elicited by delayed-type hypersensitivity, the reaction being mediated by T lymphocytes. We examined the T-cell receptor (TCR) beta-chain variable gene segment (Vbeta) use of nickel-induced CD4+ and CD8+ T cells in the peripheral blood of nickel-sensitive and nonsensitized subjects. The results show that each patient had an individual Vbeta repertoire overexpressed, these being in CD4+ cells Vbeta10 and Vbeta13 (in subject A); Vbeta1, Vbeta2, Vbeta13 and Vbeta21 (subject B); Vbeta1 and Vbeta10 (subject C); Vbeta9 and Vbeta19 (subject D). Thus, no single Vbeta gene dominated in a majority of the CD4+ samples. The Vbeta genes overexpressed in patient CD8+ nickel-induced T cells were Vbeta1 (in subject A), Vbeta1 (subject B), Vbeta1 and Vbeta2 (subject C) and Vbeta7 (subject D), domination of Vbeta1 being seen in most of the CD8+ samples (75%). No specific overexpression of any Vbeta genes in the nickel-allergic subjects was found in comparison with the non-sensitized subjects. In conclusion, an individual pattern of restricted Vbeta genes was induced with nickel in CD4+ and CD8+ T cells in each nickel allergy patient.

TAP1 and TAP2 genes in nickel allergy.

The study was undertaken to see whether TAP1 and TAP2 (transporter associated with antigen processing) genes are involved in susceptibility to nickel allergy. The products of these genes are important in antigen transport and processing, making them candidates for disease susceptibility. Fifty-five nickel-sensitive and 54 non-sensitive subjects were TAP1- and TAP2-typed by amplification refractory mutation system - polymerase chain reaction. The allele and phenotype frequencies of TAP2B were significantly (p = 0.019 and 0.012, respectively) increased in nickel-sensitive subjects versus controls. Relative risk (RR) for TAP2B was 2.7 and etiological factor (EF) = 0.46. The allele frequency of TAP2C was decreased among the nickel-sensitive subjects versus controls (p = 0.016). RR for TAP2C was 0.18. In conclusion, TAP2B increases the risk for nickel allergy, the results suggesting a considerably high EF.

HLA markers in a community-based rheumatoid arthritis series.

We wanted to investigate whether rheumatoid arthritis (RA) patients, defined by the American College of Rheumatology (ACR) 1987 criteria and selected from one community by the help of the official Finnish data registers, share the common HLA susceptibility genes. The HLA frequencies of 88 RA patients representing 85% of the prevalent cases of RA in the community were compared with those of 188 healthy controls. Fifty-four per cent of the index cases with RA had DR4 compared with 30% of the healthy controls (P <0.001). The 'RA susceptibility sequence' was found in 75% of the DRB1 genes in the index cases, but it did not correlate with the severity of the disease. The frequency of DR3 was not increased in RA patients but it was associated with features of severe disease, that is, with a high erythrocyte sedimentation rate (P<0.05), extra-articular disease (P<0.01) and prostheses in large joints (P<0.05). According to our results community-based RA patients satisfying the new ACR criteria show the common DR4 association. DR3 was the only HLA allele which showed some disease-modifying effect correlating with the severity of RA.

The frequency of QAP2.1 is increased in psoriasis vulgaris patients but no unusual linkage between QAP/DQA1 or QBP/DQB1.

Psoriasis vulgaris is a chronic skin disease with a genetic and immunological background. We have previously defined the two most frequent risk haplotypes in Finns: A2,B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201. The aim of this study was to further examine whether the flanking regions, URRs of DQ (QAP and QBP) and TAP1 and TAP2 genes are involved in susceptibility to psoriasis. The frequency of QAP2.1 was increased in psoriatics as compared with controls (Pc = 3.6 x 10(-2), RR = 5.0), and the frequency of QAP4.1 was decreased in psoriasis patients (Pc = 4.2 x 10(-2)). The frequency of the phenotype combination Val/Ile at position 379 of TAP2 was decreased in patients (Pc = 1 x 10(-2)). The allele and phenotype frequencies of TAP1 and TAP2 genes were not different between these groups. Haplotypes A2, B13,Cw6,DR7,DQA1*0201,QAP2.1 and A1,B17,Cw6, DR7,DQA1*0201,QAP2.1 are the two most frequent HLA marker haplotypes for psoriasis vulgaris in Finns, Cw6, DR7, DQA1*0201 and QAP2.1 being the most important single alleles for the risk of this disease.

HLA five-locus haplotypes in Finns.

The extreme polymorphism of HLA genes makes them a powerful tool for distinguishing between different genetic populations. Five-locus HLA haplotypes of Finns (from Oulu, Northern Finland) are described here in order to characterize further the migration pathways of the population to Finland after the Ice Age. From random families, 364 haplotypes were obtained. The most frequent Finnish haplotype A3,Cw4,B35,DR1,DQ1 (7.7%) is a Caucasoid ancestral haplotype and is shared with Italians of Celtic and non-Celtic origin. The haplotype A1,Cw7,B8,DR3,DQ2, which occurs in 4.7% of Finns, is the most frequent haplotype in Caucasoids. The haplotypes A3,Cw7,B7,DR2,DQ1 (3.6%) and A2,Cw7,B7,DR2,DQ1 (2.5%) are shared with several Caucasoid populations and the latter also with Jamaican blacks. A2,Cw5,B44,DR5,DQ3 (0.8%) is shared with Italians of Celtic and non-Celtic origin, A2,Cw6,B13,DR7,DQ2 (1.1%) with Caucasoids in the USA and A9,Cw4,B35,DR1,DQ1 (0.8%) with Mongoloids. The haplotypes A2,CW3,B62,DR4,DQ3 (3.0%), A2,Cw2,B27,DR8,DQ4 (1.7%), A2,Cw3,B62,DR6,DQ1 (1.4%) and A2,Cw1,B27,DR4,DQ3 (1.4%) were also found to be among the most frequent in the Finnish population. The most frequent HLA haplotypes are consistent with the postulated ancient migration of populations from southern Scandinavia and Germany to Finland, the most frequent haplotype suggesting a common Celtic origin and one less frequent haplotype suggesting an influence from the east.

HLA risk haplotype Cw6,DR7,DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris.

Psoriasis vulgaris has HLA associations. We have previously defined HLA-Cw6,DR7,DQA1*0201 as the central element of the risk haplotypes for psoriasis. On the other hand, Cw6 as a single gene has the strongest association with psoriasis. The aim of this study was to determine whether the risk haplotype and Cw6 correlate with the clinical parameters of the disease. The series consisted of 64 patients and the clinical parameters were age at onset, family history of psoriasis, arthritis and the frequency of inpatient treatment. The HLA risk haplotype Cw6,DR7,DQA1*0201 had previously been found in 30% and Cw6 alone in 54% of the patients. The presence of Cw6 correlated with early age at onset (Pc = 0.01). The presence of the risk haplotype correlated with a positive family history of psoriasis among the first-degree relatives (Pc = 0.02) and an overall positive family history (Pc = 0.04), but Cw6 had a stronger correlation with an overall positive family history (Pc = 0.01). There were no positive correlations with arthritis or the number of inpatient treatment periods. Only type I psoriasis was associated with Cw6 (Pc = 0.0006). In conclusion, Cw6 and the haplotype Cw6,DR7,DQA1*0201 are important in the heredity of psoriasis vulgaris, but the presence of Cw6 alone is sufficient to indicate a clinically significant risk for psoriasis.

HLA-G polymorphism and allelic association with HLA-A in a Finnish population.

The polymorphism of the HLA-G gene can be identified by PCR-RFLP analysis. This short communication describes the PCR-RFLP analysis of HLA-G polymorphisms in exons 2 and 3 and the association of different HLA-G and HLA-A alleles in 26 healthy Finnish families.

Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2,B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201.

Psoriasis vulgaris is a skin disease with an immunological and genetic background present in 1-3% of the population. We studied the genetic susceptibility to psoriasis vulgaris in Finns with serological HLA typing and genomic HLA class II typing of the DQ and DP loci to evaluate the risk of developing psoriasis. The haplotypes most frequently distinguishing between psoriatics and controls were those that carried Cw6 (P < 10(-8)), DQA1*0201 (P = 9.3 x 10(-6)) and DR7 (P = 3.9 x 10(-5)). The two most frequent marker haplotypes were A2,B13,Cw6,DR7, DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201, which were not found among the control subjects. A deficit of haplotype B8,DR3,DQ2 (2 out of 124 in the patients versus 15 out of 106 in the controls, P = 1.5 x 10(-4)) was found, and this was in accordance with a slightly decreased frequency of DQA1*0501 (P = 3.1 x 10(-2)), which was usually linked with this haplotype. These results stimulate the research for a genetic resistance factor in psoriasis. Thus, this report sheds further light on the immunogenetic background of psoriasis in Finland. We conclude that the inheritance of psoriasis has a polygenic mode, in which the Cw6,DR7,DQA1*0201 combination seems to be important (P = 7.5 x 10(-7), relative risk 24.4, aetiological factor 0.29).

Dermatophytes in northern Finland in 1982-90.

The epidemiology of human dermatophytes was studied in northern Finland in 1982-90. The samples were analysed at the Department of Medical Microbiology, University of Oulu. The total number of samples was 17,822, of which 3185 (18%) were positive. The annual number of samples and positive cultures remained relatively constant. Trichophyton rubrum was the most common species being isolated from 2101 samples (66% of all positive cultures), while Trichophyton mentagrophytes was isolated from 815 samples (26%) and Epidermophyton floccosum from 193 samples (6%). T. verrucosum caused an epidemic among cattle keepers in 1987-90, causing 47 infections. Microsporum canis, T. terrestre and T. violaceum were rare. The same species affected both children and adults. There was a tendency towards a decrease in tinea in the groin and a slight increase in tinea pedis. T. rubrum and T. mentagrophytes occurred most frequently in patients aged 41-45 years and as foot infections. E. floccosum usually affected the toe web and the groin in patients aged 21-25 years, more often infecting men. Fifty-four per cent of all positive samples came from men and 46% from women.

Adhesion molecules in the nickel allergic reaction.

Nickel is the major cause of allergic contact dermatitis, and to increase our understanding of this immune reaction we studied changes in the expression of adhesion molecules on mononuclear cells during nickel stimulation in vivo and in vitro. Nickel-induced lymphocyte cultures were used in vitro, the cells being examined with monoclonal antibodies (Mabs) and by flow cytometry. Mononuclear cells from skin biopsies of in vivo cutaneous nickel reactions were studied with Mabs and immunohistochemistry. The expression of adhesion molecules in vitro was differential: the number of cells carrying CD11c, CD29, CDw49b, CDw49d, CDw49e, CDw49f, CD54, CD56 and ELAM-1 being significantly overrepresented among the nickel-induced lymphoblasts whereas the number of blasts carrying CD44 was underrepresented and those of CD11a, CD18, CD58 and LAM-1 remained unchanged. CD4+ cells gained adhesion molecules during nickel-induced blast transformation whereas CD8+ cells lost most of their adhesion molecules. The in vivo results were in agreement with the in vitro ones except that CDw49b, CDw49f, CD56 and ELAM-1 could not be detected in a 96-hour nickel reaction in vivo. In conclusion, the nickel allergic reaction favors the expression of certain adhesion molecules, and this expression is induced on CD4+ cells while CD8+ cells tend to lose such molecules. The changes were more sensitively detected with the in vitro method.

Alanine at position 73 of HLA-C is associated with psoriasis vulgaris in Finland.

A close association was found between a specific sequence of HLA-C and psoriasis vulgaris in Finnish patients (chi 2 = 18.4, P = 1.78 x 10(-5)). This sequence codes for alanine at position 73 of the HLA-C molecule in the antigen binding cleft, and alanine may play a role in susceptibility to the disease.

Different distribution of T cell receptor beta-chain haplotypes in mixed connective tissue disease and systemic lupus erythematosus.

Mixed connective tissue disease (MCTD) and systemic lupus erythematosus (SLE) are autoimmune diseases with a genetic background, and it is reasonable to suggest that aberrations in T cell receptor (TCR) genes could contribute to these diseases, as they play an important role in immune regulation. We studied TCR beta-chain gene segments V beta 8, V beta 11 and C beta with restriction fragment length polymorphism (RFLP) in MCTD and SLE patients and controls. Haplotypes could be assigned in individuals who were homozygous for two or three of these three loci, whereupon the haplotype 2/25/10 (V beta 8/V beta 11/C beta) was found to be under-represented in MCTD (P = 0.029). The frequencies of individual alleles in both groups were similar to those of the controls, whereas the number of homozygotes within V beta 8 gene (23/23 kb and 2/2 kb) was increased in MCTD (P = 0.028). It is concluded that the distribution of TCR beta-chain genes could be aberrant in MCTD and could play a role in susceptibility, whereas the TCR beta-chain gene distribution in the SLE patients did not differ from that of the controls.