Jaakko Antonen

Genetic association between interleukin‐10 promoter region polymorphisms and primary Sjögren's syndrome

OBJECTIVE To determine whether the haplotypes formed on the basis of single-base-exchange polymorphisms at positions -1082, -819, or -592 of the interleukin-10 (IL-10) gene predispose subjects to primary Sjögrens syndrome (SS). METHODS The frequency of IL-10 polymorphisms was analyzed in 62 patients with primary SS and in 400 healthy subjects. These data were assessed for correlations with the concentration of IL-10 in the plasma. RESULTS The frequency of the IL-10 GCC haplotype (G at position -1082, C at position -819, and C at position -592 of the IL-10 gene) was increased (P < 0.05, odds ratio [OR] 1.90, 95% confidence interval [95% CI] 0.955-3.62) and the frequency of the ACC haplotype decreased (P < 0.05, OR 0.443, 95% CI 0.257-0.764) in primary SS patients compared with healthy controls. Moreover, the frequency of the ATA haplotype was similar in primary SS patients and healthy controls, but the incidence of the GCC/ATA genotype was elevated in the primary SS patients (P < 0.05, OR 2.19, 95% CI 1.19-4.03). The concentration of plasma IL-10 was significantly higher in patients carrying the GCC haplotype than in non-carriers of GCC. CONCLUSION These results suggest that the presence of the GCC haplotype or the GCC/ATA genotype and the absence of the ACC haplotype of the IL-10 gene are associated with an increased susceptibility to primary SS. This effect is probably mediated by the increased capability to produce IL-10 among carriers of the GCC haplotype.

Adequate Seroresponse to Influenza Vaccination in Dialysis Patients

Background: Hemodialysis (HD) patients are immunocompromised, and they have been shown to react suboptimally to recommended vaccinations. Advances in dialysis therapy and other supportive measures may theoretically result in better immune system functions. Clinical evidence supporting this theory has, however, not been presented. With influenza vaccination response, we tried to address this question. Methods: 42 HD and 15 continuous ambulatory peritoneal dialysis (CAPD) patients were vaccinated with a trivalent influenza vaccine, and the seroresponses at 5 weeks were measured. The results were compared with those of similarly vaccinated 20 nephrology outpatient clinic patients with varying degrees of renal insufficiency and those of 31 cardiac patients with normal renal function. Results: The dialysis patients had higher prevaccination titers of hemagglutination-inhibiting (HI) antibodies to all three vaccine virus antigens than the other groups due to more frequent previous vaccinations. The dialysis patients exhibited lower antibody increases, but an almost comparable proportion of them reached a protective antibody level (HI titers ≧40) 5 weeks after vaccination [A/H3N2: 61% (cardiac patients), 35% (nephrology outpatient clinic patients), 67% (CAPD), and 36% (HD); A/H1N1: 71, 70, 80 and 60; B: 97, 90, 80, and 76%, respectively]. Among the HD group, all patients receiving parenteral calcitriol except 1 (83%), but only 50% of the other HD patients produced protective antibody titers at least to two out of three vaccine virus antigens. No other patient- or HD treatment-associated parameter was significantly related to the vaccination-induced antibody response. Conclusions: We conclude that influenza vaccination of dialysis patients according to current recommendations may be effective. Additionally, our results suggest that parenteral calcitriol treatment may augment the immune response of HD patients even in a clinically relevant way, an effect so far shown only in in vitro studies.

DIVERSITY OF CLINICAL SPECTRUM OF HTLV-III INFECTION

In a prospective follow-up volunteer study lasting 4 to 16 months, 17 of 200 homosexual men living in Finland had antibodies to human T-lymphotrophic virus type III (HTLV-III). 1 man who initially had a low titre of HTLV-III antibodies became seronegative within 6 months without any symptoms developing, and a seronegative man became seropositive. 14 men had high titres of HTLV-III antibodies when they first joined the study and during the study titres rose in all other HTLV-III-positive men except those with AIDS. Initially 9 men were symptom-free, 3 had lymphadenopathy syndrome (LAS), 3 had AIDS-related complex (ARC), and 2 had AIDS. During follow-up LAS developed in 3 symptom-free HTLV-III positive men but none of those with LAS or ARC progressed to AIDS. Most HTLV-III-positive men, including those who were otherwise symptom-free, had mucocutaneous lesions generally associated with immune deficiency. Regardless of the symptoms, those with increasing HTLV-III antibody titres showed lowered T helper/T suppressor ratios, decreased numbers of T helper cells, and/or diminished responses to tuberculin antigen (PPD). These results suggest that the clinical spectrum of HTLV-III infection ranges from transient infection through chronic provirus state, asymptomatic virus producer state, LAS or ARC, and rarely full-blown AIDS. Cofactors probably determine the final outcome of infection in the individual.

Oral candidal infection as a sign of HIV infection in homosexual men

The oral mucosae of 66 homosexual men were examined clinically and by means of cultivation to determine the presence of Candida infection. In addition, clinically detected mucosal changes were recorded and a biopsy specimen was obtained for the histopathologic classification. A total of forty one subjects (62%) showed clinical evidence of candidiasis. Fourteen (21%) of the sixty-six men were seropositive for human immunodeficiency virus (HIV). A total of thirteen of fourteen (93%) of the seropositive men and twenty-six of fifty-two (50%) of the HIV seronegative men had culture-confirmed oral candidiasis. In the latter group, oral candidiasis was clearly correlated to cigarette smoking. Clinical mucosal changes other than candidiasis were found in forty-five of the sixty-six subjects studied. The most frequent finding was trauma resulting from biting, which was usually localized on the cheek. Leukoplakia was found in twelve of sixty-six subjects, while cauliflower-like condylomas were present in 4 persons. The results emphasize the frequent occurrence of different oral lesions in subjects seropositive for HIV and in those at high risk for HIV infection. Oral examination in search for potential early manifestations of HIV infection in homosexual men is advocated.

IgM-associated glomerulonephritis.

In a series of 374 renal biopsy specimens, 26 from patients with primary glomerulonephritis showed IgM as the main glomerular immunofluorescence finding. By light microscopy 17 of these specimens showed mild mesangial hypercellularity and 9 were normal. Small mesangial electron-dense deposits were seen in 8 specimens. Of the 26 patients, 10 had proteinuria, 6 had the nephrotic syndrome, 6 had hematuria and 4 had both proteinuria and hematuria. The mean serum IgM level was significantly higher in the patients than in healthy controls. Circulating immune complexes were detected by three methods in 39% of the patients.

A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant

Abstract A patient with severe capillary leakage syndrome caused by a Puumala hantavirus infection was treated with a single dose of icatibant, a bradykinin receptor antagonist, with a dramatic positive response. We suggest that this drug should be tested in a larger number of patients with severe hantavirus infection.

Adverse drug reactions in Sjögren's syndrome. Frequent allergic reactions and a specific trimethoprim-associated systemic reaction.

Trimethoprim-associated systemic reactions, including aseptic meningitis, have been reported to be very rare adverse drug reactions. Patients with Sjögrens syndrome have been overrepresented, but no epidemiological surveys of the reaction have been conducted. To study the overall frequency of adverse drug reactions, and especially trimethoprim-associated reactions, we interviewed 85 primary Sjögrens syndrome patients and compared the results with those of 45 similarly interviewed osteoarthritis patients. Antimicrobial allergy was more common among Sjögrens syndrome patients than in osteoarthritis patients (46% vs. 27%). Eleven Sjögrens syndrome patients (13%), but no osteoarthritis patient, had experienced at least a partial, non-allergic systemic reaction with trimethoprim. Of them five (6%) had had a full-blown systemic reaction including both chills/fever and headache/backache and at least one of the following: malaise, vomiting, dizziness, confusion or meningeal irritation. Our findings confirm that allergic reactions to antimicrobials are frequent in Sjögrens syndrome. In addition to allergic reactions Sjögrens syndrome patients are prone to a specific trimethoprim-associated systemic reaction. This should be remembered when prescribing antimicrobials.

The significance of mannan-binding lectin gene alleles in patients with primary Sjögren's syndrome.

Objective and methods : To investigate the significance of mannan-binding lectin (MBL) gene alleles in patients with primary Sjögrens syndrome (pSS). Genotypes were determined in 65 pSS patients and 138 controls. Results : No difference in MBL genotype or allele frequencies was detected between the pSS patients and controls. However, when the effect of MBL genotypes on the diagnostic findings in pSS patients was assessed, none of the eight patients with 52/w genotype fulfilled four (definite) Californian criteria (P= 0.007). Among these eight the Chisholm-Mason histological grade was f 3 in only three (P= 0.017). Furthermore, the MBL concentration was lower in patients with 52/w genotype compared to those with wild-type (w/w) genotype (P= 0.035). Conclusion : Our findings suggest that MBL structural gene polymorphisms do not influence on susceptibility to pSS. However, MBL may be associated with salivary gland destruction in pSS, and its concentration may be comparable with the intensity of inflammatory reaction. Further studies are warranted to clarify the possible mechanisms involved.

Pathophysiology of a severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.

We recently described a patient with very severe Puumala hantavirus infection manifested by capillary leakage syndrome and shock. He was successfully treated with the bradykinin receptor antagonist, icatibant (Antonen et al., 2013). Here we report analysis of the pathophysiology which indicated pronounced complement activation, prolonged leukocytosis, extensive fibrinolysis, circulating histones, and defects in liver function. The patient had an uncommon HLA-phenotype, which may have contributed to the severe course of the disease.

Intravenous Calcitriol Therapy Restores Reduced Antigen-Induced T-Lymphocyte Response in 1,25-(OH)2D3-Deficient Hemodialysis Patients

Ten hemodialysis patients were treated with intravenous calcitriol (1-1.5 micrograms 3 times per week) for 3 months and parameters reflecting cell-mediated immunity were measured before and at the end of treatment. Peripheral blood CD4+ cells increased from 33.1 +/- 14.2 to 43.8 +/- 5.8% (p < 0.05) causing a comparable increase in CD3+ cells (67.3 +/- 14.3 vs. 77.1 +/- 7.9%, p < 0.05), whereas CD8+ cells did not change significantly (22.2 +/- 5.4 vs. 25.5 +/- 3.0%). Mitogen-induced lymphocyte stimulation responses were normal even before treatment and did not change. Antigen-induced T-cell responses were very heterogeneous before calcitriol therapy; those 5 with initially unmeasurably low serum 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) had a weaker response than the other patients (3,873 +/- 1,528 vs. 22,948 +/- 13,684 cpm, p < 0.05). After calcitriol treatment the patients with pretherapy unmeasurably low serum 1,25-(OH)2D3 had a comparable response to other patients (16,220 +/- 9,674 vs. 22,064 +/- 10,331 cpm). Our study shows that calcitriol therapy restores the depressed antigen-induced T-cell response of the hemodialysis patients most deficient in 1,25-(OH)2D3.