Biomedical subjects

S Albani

Publications and source records attributed to S Albani.

32 records · Page 2Linked to original sources

PubMed1992

Molecular basis for the association between HLA DR4 and rheumatoid arthritis. From the shared epitope hypothesis to a peptidic model of rheumatoid arthritis.

Susceptibility to rheumatoid arthritis (RA) maps to residues QKRAA/QRRAA in the third hypervariable region of the HLA DR beta 1 chain. Peptides from the same area of MHC class II molecules are able to modulate the T-cell repertoire by deleting self-reactive T-cells. The Epstein Barr virus glycoprotein gp110 and the dna J heat-shock protein from E. coli mimic the third hypervariable region of HLA-Dw4DR beta 1. Thus, the same area of HLA DR beta 1 carries susceptibility to RA, modulates the T-cell repertoire and is mimicked by human pathogens. RA may originate from a particular shape imposed on the T-cell repertoire by the QKRAA/QRRAA sequence in the third hypervariable region of HLA DR beta 1.

Amino Acid Sequence↗

PubMed1992

Recurrent juvenile dermatomyositis and cutaneous necrotizing arteritis with molecular mimicry between streptococcal type 5 M protein and human skeletal myosin.

An adult patient had a syndrome associating the features of juvenile dermatomyositis and cutaneous polyarteritis nodosa that followed a cyclic course from childhood; recurrences were always associated with a rise of serum antistreptococcal antibodies. Regions of homology between streptococcal type 5 M protein and skeletal myosin were found. These findings suggest that streptococcal infection, possibly through a molecular mimicry mechanism, played a role in the pathogenesis of the disease in our patient.

Acute Disease↗

PubMed1992

The susceptibility sequence to rheumatoid arthritis is a cross-reactive B cell epitope shared by the Escherichia coli heat shock protein dnaJ and the histocompatibility leukocyte antigen DRB10401 molecule.

Immunological responses to bacterial heat shock proteins have been implicated in the pathogenesis of arthritis in animals and humans. The predicted amino acid sequence of dnaJ, a heat shock protein from Escherichia coli, contains an 11-amino acid segment that is homologous to the third hypervariable region of the human histocompatibility antigen (HLA) DRB10401 (formerly known as HLA Dw4), the part of the molecule that carries susceptibility to rheumatoid arthritis. To test the biological significance of this finding, we expressed and purified recombinant dnaJ (rdnaJ), and determined its immunologic cross-reactivity with HLA DRB10401. A rabbit antipeptide antiserum raised against the sequence of the third hypervariable region of HLA DRB10401 specifically bound to 'dnaJ, thus confirming that a similar sequence is expressed on the bacterial protein. Of greater consequence, an antiserum to the 'dnaJ protein recognized not only a peptide from the third hypervariable region of HLA DRB10401, but also the intact HLA DRB10401 polypeptide. Furthermore, the antibody to 'dnaJ reacted with HLA DRB10401 homozygous B lymphoblasts, but not with HLA DRB11501, DRB10101, DRB10301, and DRB10701 (formerly known as HLA Dw2, DR 1, DR 3, and DR 7, in the same order) homozygous cells. These results demonstrate that exposure to a bacterial heat shock protein can elicit antibodies against the rheumatoid arthritis susceptibility sequence in the third hypervariable region of HLA DRB10401.

Amino Acid Sequence↗

PubMed1992

Genetic and environmental factors in the immune pathogenesis of rheumatoid arthritis.

Our experiments have led us to conclude that the rheumatoid arthritis shared epitope may act as a peptide that is important for positive and negative selection of T lymphocytes, that T lymphocytes are skewed by positive selection to recognize epitopes that are similar but not identical to self, and that peptide sequences that are similar to the RA-shared epitope are abundantly expressed by microorganisms that chronically infect most people. This combination of events could partly explain the association of the shared epitope with the severe forms of RA. The hypothesis cannot be tested directly, because we do not postulate that any unique population of autoreactive T cells is expanded in RA; however, the role of positive selection in molding the human T-cell repertoire to exogenous antigens can be tested by mapping T-cell antigenic determinants on the E. coli dnaJ protein or the gp110 protein of EBV in people with different HLA-DR types. Moreover, positive selection models imply that maternal antigens that cross the placenta can influence the T-cell repertoire. Thus, one might expect to find that the frequency of HLA-DR4 in the mothers of patients with RA who themselves lack the DR4 antigen, would be more frequent than predicted by chance alone. As the principles of positive selection are more precisely delineated in animal systems, it should become possible to ascertain more clearly how the shared epitope on HLA-DR molecules enhances the severity of autoimmune reactions; however, RA only occurs in humans; possibly because of the unique inability of human macrophages to replicate. Thus, only the direct analysis of patients can directly reveal the mechanisms of disease pathogenesis.

Arthritis, Rheumatoid↗

PubMed1991

Tolerance to a self peptide from the third hypervariable region of the Es beta chain. Implications for molecular mimicry models of autoimmune disease.

As a first step in the analysis of a molecular mimicry model of rheumatoid arthritis, we addressed the question of whether tolerance to self-major histocompatibility complex (MHC) class II molecules includes tolerance to peptides from the third hypervariable region of their beta chain. We studied T cell responses to a peptide from the third hypervariable region of the Es beta chain, Es beta peptide (PEFLEQRRAAVDTYC), in different mouse strains after footpad priming with peptide in complete Freund's adjuvant. Strains of mice of the k or d haplotype (B10D2; H-2d, B10BR; H-2k) mounted a vigorous T cell response to the Es beta peptide. In mice expressing the Es beta chain either on the cell surface (B10S9R) or in the cytoplasm as free unassociated chain (B10S), no response could be detected. Binding studies using purified MHC class II molecules and competition for antigen presentation showed that the Es beta peptide binds Ak, Ad and As but not Ek. Thus, the nonresponder status of B10S and B10S9R mice appears to reflect self tolerance. Tolerance was also suggested by the observation that responder x nonresponder F1 crosses such as (B10D2 x B10S9R) and (B10BR x B10S9R) did not respond to Es beta peptide. Interestingly, mice derived from the (B10BR x B10S) cross responded to the Es beta peptide, suggesting that the immune system may not always tolerate peptides from the third hypervariable region of self-MHC class II molecules.

Amino Acid Sequence↗

PubMed1991

Immune response to peptides from the third hypervariable region of the beta chain of MHC class II molecules. Implications for the immune response to foreign antigens.

To understand the biologic significance of amino acid sequence sharing between proteins from pathogens and hypervariable regions of HLA DR molecules, we studied the immunological status of a peptide from the third hypervariable region of IEb, the mouse equivalent of HLA DRb. We found that allo MHC peptides are recognized and self MHC peptide is tolerated. This suggests that MHC class II molecules may modulate the T cell repertoire not only by selective binding of antigenic peptides (determinant selection) but also by deleting or inactivating T cells specific for self MHC peptides. In the human, such a mechanism may explain why some HLA DR4 subjects have a deficient control of EBV infection.

Amino Acid Sequence↗

PubMed1990

Antihistone antibodies in antinuclear antibody-positive juvenile arthritis.

The binding of antinuclear antibody-positive juvenile arthritis (JA) sera to bovine thymus histones H1, H2A, H2B, H3, and H4 was studied by an enzyme-linked immunosorbent assay. Seventy-five percent of the JA patients tested positive for at least 1 antibody specificity. Antihistone antibodies were predominantly IgM, while IgG antibodies were less common and were restricted to histones H1 or H3. In the group of patients with JA of pauciarticular onset, antihistone antibodies were significantly more elevated in patients with past or present uveitis than in patients without a history of uveitis. Anti-H1 antibodies in JA patients were found to react mostly with determinants located in the carboxyl-terminal domain of the H1 molecule. Sera were also reactive with human histone H1(0) or chicken histone H5, which are H1 variants found only in nondividing cells.

Adolescent↗

PubMed1990

Antibody reactivity against single stranded DNA of various species in normal children and in children with diffuse connective tissue diseases.

The aim of this work was to study possible differences in the humoral response against autologous and heterologous (bacterial and mammalian) ssDNA in children with diffuse connective tissue diseases (DCTD) compared with age matched controls. We found that IgM anti ssDNA were significantly increased in systemic lupus eritematosus (SLE) and in juvenile arthritis (JA), but not in juvenile dermatomyositis (JDM). IgG anti ssDNA were significantly elevated only in children with SLE. We next evaluated the binding specificity to human and bacterial ssDNA by inhibition assays. We found that SLE and JA sera recognised epitopes shared in common to endogenous and bacterial ssDNA. In contrast, in normal subjects IgG binding to bacterial DNA was not inhibited by human DNA, while IgG anti human ssDNA were cross reactive with the bacterial antigen. These data suggest that natural antibodies (IgM) producing cells are activated in some but not all DCTD, and that normal children have different reactivity against autologous and heterologous ssDNA with respect to SLE and JA patients.

Adolescent↗

PubMed1989

Diagnostic value of a lymphocyte stimulation test in cow milk protein intolerance.

In order to evaluate the diagnostic value of a lymphocyte stimulation test with casein and beta lactoglobulin in cow milk intolerance (CMI), we studied 26 patients with a diagnosis of CMI and 25 age-matched controls with intestinal diseases other than CMI. Lymphocyte stimulation test to casein (P less than .001) and beta lactoglobulin (P less than .001) was significantly higher among CMI patients. Seventeen patients were RAST positive and nine negative for whole milk proteins. No differences were found in the lymphocyte stimulation test response between RAST-positive and RAST-negative subjects. These results suggest that lymphocyte stimulation test with highly purified antigens in optimal concentrations is specific and could be useful in the diagnosis of CMI.

Animals↗

PubMedDate not supplied

Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis.

We measured serum and synovial fluid interleukin 6 (IL-6) levels in patients with polyarticular-onset and pauciarticular-onset juvenile chronic arthritis (JCA), using the hybridoma cell line B9. During active disease, but not during remission, serum IL-6 levels were significantly elevated in patients with polyarticular (p < 0.0001 vs controls) and in patients with pauciarticular JCA (p < 0.01 vs controls). In patients with active polyarticular disease (polyarticular and extended pauciarticular) serum IL-6 levels correlated with the extent and severity of joint involvement (p < 0.05), with erythrocyte sedimentation rate values (p < 0.005) and with C reactive protein concentrations (p < 0.05). In patients with persistent pauciarticular JCA, serum IL-6 levels correlated with the joint swelling score (p < 0.05). Synovial fluid IL-6 levels, measured in 5 patients with pauciarticular JCA, were markedly elevated (range 600-24,000 HGF U/ml). In conclusion, our data suggest that IL-6 is an important pathogenic mediator in polyarticular and pauciarticular JCA.

Adolescent↗

PubMedDate not supplied

[Changes in the production of IgM in response to pokeweed mitogen in juvenile rheumatoid arthritis. Correlations with disease activity].

Unstimulated and pokeweed mitogen (PWM)-stimulated "in vitro" IgM synthesis by peripheral blood lymphocytes has been evaluated by an ELISA method in 33 patients with juvenile rheumatoid arthritis (JRA). Lymphocyte PWM responses were significantly reduced in patients with JRA compared with healthy controls. When patients were divided according to disease activity, a significant increase of stimulation index (ratio of IgM synthesis with over that without PWM) has been observed in patients with disease remission compared with those with active disease. These findings confirm the defect in PWM-induced IgM synthesis by peripheral blood lymphocytes of patients with JRA and suggest that these abnormalities may be related to disease activity.

Adolescent↗

PubMedDate not supplied

Autoantibodies in juvenile dermatomyositis.

Fourteen patients with juvenile dermatomyositis (JDM) have been investigated for the presence of several serum autoantibodies: antinuclear (ANA), anti-single-stranded and double-stranded DNA, anti-histones, anti-Sm, anti-ribonucleoprotein, anti-SSA/SSB, anti-PM-1, anti-Jo-1, anti-mitochondrial, anti-smooth muscle, anti-gastric parietal cells, anti-cardiolipin (ACA) antibodies and rheumatoid factor. Patients were negative for all autoantibodies except for ANA and ACA. ANA were detected in 50% of the patients when tested on rat liver, but the percentage of positivity rose to 86% when HEp-2 cells were used as substrate. This finding suggests that HEp-2 cells represent a more sensitive substrate than rat liver for the detection of ANA in JDM. Three patients were positive for ACA; two of these presented vascular complications, thus suggesting a possible relationship between ACA and vascular involvement in JDM.

Antibodies, Antinuclear↗

PubMedDate not supplied

Infection and molecular mimicry in autoimmune diseases of childhood.

The etiopathogenesis of childhood chronic autoimmune disease is, in most cases, unknown. Most likely, several factors overlap in determining the loss of tolerance toward certain autoantigens that become the target of the disease and the main cause of its perpetuation. Infectious agents have often been implicated in the pathogenesis of these diseases, but, to date, compelling evidence for a horizontal transmission or for localized epidemics is lacking. Human pathogens may nevertheless play a role in determining the loss of tolerance toward certain self-antigens by means of mechanisms other than classic infection. It is common knowledge that human pathogens often express proteins with high antigenic potential with important homologies with human proteins. Evolutionary pressures based upon the necessity of escaping the host's specific immune responses may have determined this phenomenon, called "molecular mimicry". It is reasonable to assert that certain individuals can develop abnormal immune responses upon contact with an antigen that mimics a self-protein. These responses may ultimately lead to self-reactivity and autoimmune disease. In this model of molecular mimicry, self-reactivity is triggered by cross-recognition of a self and an exogenous protein that bear the same sequence. A disease triggered by such a mechanism should present with: i) some form of an acute or chronic autoimmune clinical manifestation; ii) a documented clinical correlation between contact with a human pathogen and the autoimmune disease; iii) immune cross-reaction between a protein from a pathogen and a homologous human protein. Acute rheumatic fever, Reiter's syndrome and the other reactive arthritides fulfill the above conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMedDate not supplied

Anti-double stranded DNA, anti-histone, and anti-nucleosome IgG reactivities in children with systemic lupus erythematosus.

In this study we evaluated the presence of anti-nucleosome reactivity in children with systemic lupus erythematosus (SLE), and assessed its clinical correlations in comparison with anti-dsDNA and anti-histone IgG levels. Reactivities to nuclear substrates were determined by enzymatic immunoassays in 80 sera from 22 children with SLE, and solid phase adsorption experiments were performed. In children with active SLE, the anti-dsDNA, anti-histone, and anti-nucleosome IgG levels were elevated, and were significantly correlated with disease severity; during remission anti-histone (but not anti-dsDNA and anti-nucleosome) antibodies, although reduced, were still significantly elevated. The results of adsorption studies showed that anti-dsDNA antibodies contributed to anti-nucleosome reactivity, while anti-histone antibodies did not. The recognition of the H3H4-DNA nucleosome subparticle, rather than H2AH2B-DNA, may be related to the nucleosome reactivity. In children with SLE anti-nucleosome reactivity is present; it is in part due to anti-dsDNA antibodies and in part to antibodies recognizing conformational epitopes that may be related to the H3H4-DNA nucleosome subparticle. Its clinical significance for diagnosis is not greater than that of the anti-dsDNA antibodies.

Adolescent↗