Anti-cyclic citrullinated peptide antibodies and rheumatoid factor sera titers in leprosy patients from Mexico.

Leprosy offers a broad spectrum of altered immunological sceneries, ranging from strong cell-mediated immune responses seen in tuberculoid leprosy (TT), through borderline leprosy (BB), to the virtual absence of T cell responses characteristic in lepromatous leprosy (LL). The exact mechanism of autoantibodies production remains unknown in leprosy and other chronic inflammatory diseases and also the contribution of these antibodies to the pathogenesis of the disease. The aim of this study is to evaluate the frequency and profiles of serum anti-cyclic citrullinated peptide antibodies (a-CCP), rheumatoid factor (RF) and its relationship with leprosy spectrum. Serum samples from 67 leprosy patients (54 LL, 5 TT and 8 BB) and 46 clinically healthy subjects (CHS) from the same endemic region were investigated. The clinical chart and questionnaire were used to obtain clinical information. Anti-cyclic citrullinated peptide antibodies (a-CCP) were measured by enzyme-linked immunosorbent assay, whereas the rheumatoid factor (RF) levels were measured by nephelometric method. The mean age of patients was 51.5 ± 13 years. Sera levels of a-CCP where higher in leprosy patients than in CHS (5.9 ± 11.6 vs. 0.3 ± 0.29) (P < 0.0001); the same pattern was found for RF sera titers without reaching statistical significance (16.8 ± 22.5 vs. 9.9 ± 3) (P = NS). We did not find a correlation between a-CCP and RF Rho =0.02786 (IC 95%) P = 0.8229. However, LL patients had higher a-CCP and RF levels than TT patients. Although an absence in correlation was observed, the serum levels of a-CCP antibodies and RF appeared to be useful in distinguishing LL from TT patients with a limited significance in detecting reactional leprosy patients.

Specific and nonspecific aspects of humoral immune response in leprosy.

1. We have studied some generic and specific aspects of the humoral immune response in 96 patients with leprosy (29 paucibacillary and 67 multibacillary individuals). We determined serum immunoglobulins (IgM, IgG and IgA), CH50, C1q, C3 and C4, circulating immune complexes (CIC), C-reactive protein (CRP), rheumatoid factor (RF) and antinuclear antibodies. No specific pattern of general humoral immune changes could be observed. 2. The specific immune response was studied by the detection of specific IgM anti-M. leprae antibodies. An immunoradiometric assay (IRMA) and an ELISA were compared for clinical effectiveness. IRMA showed greater sensitivity for the serodiagnosis of leprosy as compared to ELISA (88.1% vs 58.2% for multibacillary patients and 20.7% vs 10.3% for paucibacillary leprosy patients). Specificity was 96% for IRMA and 97% for ELISA. 3. Our results indicate that nonspecific changes in the humoral immune response are of little value in assessing leprosy patients and that immune assays for the detection of specific anti-M. leprae antibodies may be of value in the diagnosis, study and follow-up of these patients.

Human monoclonal antibodies to phenolic glycolipid-1 from leprosy patients cross react with poly(ADP-ribose), polynucleotides and tissue bound antigens.

Antibodies which bind to poly(ADP-ribose) have been described in Systemic Lupus Erythematosus (SLE) and a variety of infectious diseases. Two IgM kappa human monoclonal antibodies (MAbs), TH3 and PR4, produced from the fusion of peripheral blood lymphocytes of leprosy patients with the GM4672 lymphoblastoid cell line, were found to bind to poly(ADP-ribose) in direct binding and inhibition ELISAs. Significant inhibition of binding of these MAbs to poly(ADP-ribose) occurred with phenolic glycolipid-1, the M. leprae specific glycolipid, ssDNA, dsDNA, poly(dT), as well as poly(ADP-ribose) itself. Up to 80% of binding of TH3, and 90% of binding of PR4, to poly(ADP-ribose) was inhibited by 10 mcg of ssDNA suggesting that there may be sharing of some conformational determinants. Although the serological binding profiles of TH3 and PR4 are similar, only PR4 was found to bind to basal keratinocytes of normal human interfollicular epidermis and astrocyte cytoplasm in normal brain tissue. These results support the concept that an antibody binding site may accommodate more than one epitope. Furthermore, small differences in antigen binding potential may distinguish relatively innocuous antibodies from those which may be more pathogenic.

Symposium on the immunodiagnosis of rheumatic and related diseases, Part II. Rheumatoid factors.

Human rheumatoid factors are antibodies of IgG, IgA, or IgM class that show reactions with antigenic determinants present on other immunoglobulin molecules. The most commonly measured rheumatoid factor relates to the 19S IgM type, which reacts by agglutination of latex particles coated with 7S IgG and is often measured in the standard latex fixation test. Approximately 65 to 70 per cent of patients with rheumatoid arthritis show positive serologic tests for rheumatoid factor; however, a number of other chronic disease conditions are also associated with positive rheumatoid factor reactions, including infective endocarditis, sarcoidosis, leprosy, and other hyperglobulinemic conditions. Although extensive serologic and immunochemical studies have identified a number of specific antigenic structural sites on immunoglobulin molecules that react with rheumatoid factors, recent studies have shown that a certain proportion of such antibodies may show cross-reactivity with DNA-histone complexes as well. It is still not entirely clear how rheumatoid factors fit into the pathogenesis of rheumatoid arthritis itself.

Serum immunoglobulins an autoantibodies during and after erythema nodosum leprosum (ENL).

Sera from 20 patients with lepromatous leprosy complicated by erythema nodosum leprosum (ENL) were collected at the time of acute reaction and then after clinical cure four weeks later. Anti-ENL drugs used were: prednisolone (11 patients), chloroquin (6 patients), and clofazimine (3 patients). Immunoglobulins M, G, and A and autoantibodies, namely, antithyroglobulin antibody (ATA), antinuclear antibody (ANA), and rheumatoid factor (RF), were measured in these 20 paired serum samples. The mean serum concentration of IgG showed a significant elevation after clinical subsidence of the reaction, mainly in the prednisolone treated group; while those of IgM and IgA varied only marginally. Autoantibodies were detected in nine patients. Of these, three patients developed these antibodies only after remission of the reaction. Treatment with prednisolone and chloroquin, although causing subsidence of ENL, resulted in an increased incidence of ATA and/or ANA. Furthermore, it was observed that longer duration of illness, higher age group, and history of repeated attacks of ENL predisposed these patients to enhanced autoantibody formation.

Soluble immune complexes in human disease.

The great variety in biochemical properties of immune complexes occurring in human and animal disease states has made the detection of such complexes a difficult task. Variability in immune complex size, specificity, and interaction with humoral or cellular receptor systems, such as complement and phagocytes, suggests different pathogenic properties. The introduction of radioimmunoassays and the recently improved knowledge of the immune complex-receptor interactions have lead to the description of a large number of detection procedures, which in turn has widened the catalogue of diseases associated with immune complexes. This widespread occurrence of soluble immune complexes has lead many investigators to think that such complexes may occur either as a transient physiological phenomenon, important for fast clearance of the antigen, or as primary pathogenic factors triggering inflammatory reactions. Among the 50 procedures for immune complex detection known today, the article will select some pertinent tests, which will be discussed with respect to their specificity, sensitivity, and reproducibility. Furthermore, it is well known that when applied to the study of a patient group with one particular immune complex disease, various tests will result in different percentages of patients having complexes. This observation is due to differences in the underlying principle on which the various tests are based. Thus immune complexes must be further characterized with respect to their size, to the antibody class or specificity involved and, most difficult, to the antigenic specificity which participates in the complex. Recent advances in such experimental characterization of immune complexes in vitro and in the clinical evaluation of patients with complement activation associated to the presence of immune complexes will be discussed.