Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome.

Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-ß and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment.

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A-producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

Propensity to excessive proinflammatory response in chronic Lyme borreliosis.

The clinical course of Lyme borreliosis is extremely variable. However, all the clinical manifestations, acute or chronic, are characterized by strong inflammation. Borrelia burgdorferi can induce the production of several proinflammatory and anti-inflammatory cytokines. The aim of our study was to find out whether the balance between inflammatory and regulatory mechanisms is important in determining the course of Lyme borreliosis. 13 patients with early Lyme borreliosis, 8 patients with chronic Lyme disease with neurological or joint manifestations, and 15 age- and sex-matched healthy controls were studied. Chronic forms of Lyme borreliosis were characterized by stronger TNF-alpha response by monocytes to lipopolysaccharide as well as to borrelia antigen compared to early Lyme borreliosis and the healthy state. The percentage of IL-10-secreting monocytes in response to borrelia lysate was lower in the Lyme borreliosis patients than in healthy controls. The percentage of CD4(+) CTLA-4(+) regulatory T cells showed the highest values in early Lyme borreliosis. We conclude that chronic forms of Lyme borreliosis can evolve due to an aberrant innate proinflammatory response.

Serological description of Estonian patients with Lyme disease, a comparison with control sera from endemic and non-endemic areas.

Serological tests for Lyme disease are mostly not well standardized and cases of misinterpretation of test results by clinicians are rather common. The diagnostic value of serologic tests may also depend on the seroepidemiological situation of the population. The aim of the study was to compare the immunoblot pattern of Lyme borreliosis patients and control sera from endemic and non-endemic regions and to identify the most suitable interpretation criteria for our immunoblot test. Serum samples of 24 Estonian patients with Lyme disease, 12 sera from patients with tick-borne encephalitis, 40 Estonian control sera, and sera from 50 Laplanders from North Sweden where people usually never come into contact with ticks were tested for IgG antibodies to Borrelia. Sonicated lysate of Borrelia afzelii (strain ACA1) was used in immunoblot as source of antigens. In our test system the following interpretation criteria gave the specificity of 96% for Estonian population: > or = 1 band from p58, p21, p17 and p14 plus > or = 2 bands from p83/100, p39, p34, p30 and p25; or > or = 4 bands from p83/100, p39, p34, p30 and p25. The comparison of Estonian controls with Laplanders showed that subclinical infections with Borrelia are rather common in Estonia. Also the rate of other infections, giving rise to cross-reactive antibodies, may be more frequent in Estonians. The frequent reactions with Borrelia antigens in a healthy population complicate the serodiagnosis of Lyme disease.

IgG from patients with liver diseases inhibit mitochondrial respiration in permeabilized oxidative muscle cells: impaired function of intracellular energetic units?

The effect of IgG purified from the sera of healthy persons and patients with primary biliary cirrhosis (PBC) and chronic hepatitis (CH) on ADP dependent respiration (oxidative phosphorylation) in skinned muscle fibers from rat oxidative muscles (heart and M. soleus) and glycolytic skeletal muscle (M. gastrocnemius) was studied. The results show that IgG from three different sources inhibited the rate of respiration by 13, 44 and 42%, respectively, these effects being equally expressed in both types of oxidative muscles, whereas no inhibition was observed in glycolytic muscle. The following washout of unbound IgG did not abolish the inhibition of respiration suggesting that the specific interaction of IgG with antigens had taken place. Laser confocal analysis revealed binding of IgG predominantly to the sarcomeric structures such as Z-disk and M-lines in the cardiomyocytes. The staining of IgG within Z-disks and intermitochondrial space coincided throughout the muscle cells so that transversally serial spaces, each containing mitochondria and adjacent sarcomere, became clearly visible. When the IgG from a CH patient was incubated with the skinned myocardial fibers of the desmin knockout mice, its binding to Z-disks and the sarcomeric area was found to be similar to that in normal cardiac muscle. However, the transversal staining pattern was disintegrated, because of the slippage of the myofibrils in relation to each other and accumulation of mitochondria between them. These observations support the recent hypothesis that in oxidative muscles the mitochondria and adjacent sarcomeres form complexes, termed as the intracellular energetic units, ICEUs. Moreover, they indicate that human autoantibodies can be useful tools for localizing the proteins responsible for formation of ICEUs and modulation of their function. Thus, it appears that the proteins associated with the Z-disks and M-lines may participate in formation of ICEUs and that binding of IgG to these proteins decreases the access of exogenous adenine nucleotides to mitochondria, which manifests as decreased rate of ADP-dependent respiration.