A historical essay on detection of anti-neutrophil cytoplasmic antibodies.

In this essay we describe a number of the known and not so known experiences of the early anti-neutrophil cytoplasmic antibodies (ANCAs) days, explaining why and how we reached consensus on the standard indirect immunofluorescence (IIF) techniques, the naming of the two principal C- and P-ANCA patterns, why we chose to use IIF as the standard technique, how the solid phase assays have developed and where we stand today, the use of ANCA for diagnosis and the importance of using several techniques for that purpose, how ANCA titres are related to disease activity and the clinical impact of this, and finally the implications of ANCA being a natural, polyclonal antibody response against various epitopes in relation to diagnostics and disease patterns.

Mouse models for multiple sclerosis: historical facts and future implications.

Multiple sclerosis (MS) is an inflammatory and demyelinating condition of the CNS, characterized by perivascular infiltrates composed largely of T lymphocytes and macrophages. Although the precise cause remains unknown, numerous avenues of research support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Pathologically similar lesions to those seen in MS can be induced in laboratory rodents by immunization with CNS-derived antigens. This form of disease induction, broadly termed experimental autoimmune encephalomyelitis, is frequently the starting point in MS research with respect to studying pathogenesis and creating novel treatments. Many different EAE models are available, each mimicking a particular facet of MS. These models all have common ancestry, and have developed from a single concept of immunization with self-antigen. We will discuss the major changes in immunology research, which have shaped the EAE models we use today, and discuss how current animal models of MS have resulted in successful treatments and more open questions for researchers to address.

COL4A3 founder mutations in Greek-Cypriot families with thin basement membrane nephropathy and focal segmental glomerulosclerosis dating from around 18th century.

Mutations in the COL4A3/COL4A4 genes of type IV collagen account for about 40% of cases of thin basement membrane nephropathy, a condition that is estimated to affect 1% or more of the general population. We recently described 10 Cypriot families with familial hematuria and thin basement membrane nephropathy in the presence of focal segmental glomerulosclerosis, with founder mutations on COL4A3 gene. Seven of the families carried mutation G1334E on haplotype K, and another three carried mutation G871C on haplotype Ky. In this report we performed extension of the haplotypes with additional polymorphic markers, 12 for haplotype K and 22 for haplotype Ky, to estimate the linkage disequilibrium value between the mutation and flanking noncommon markers. Haplotype Ky extended to 13.71 Mb, but we did not attempt further analysis owing to the small number of chromosomes. Haplotype K extended to 3.83 Mb, thereby suggesting that it was a much older event compared to mutation G871C. Mutation G1334E was calculated to be about 5-10 generations old with a possible origin between 1693 and 1818 AD, during the Ottoman ruling of the island. Both mutations are clustered in specific geographic regions with apparently formerly isolated populations, although mutation G1334E has been detected elsewhere on the island. The identification of founder mutations in large families with microscopic hematuria greatly facilitates presymptomatic diagnosis and provides useful information on the history of the population, while it may also assist in association studies in search for disease modifier genes.

Anti-scl-70.

OBJECTIVE: To develop an overview focusing on the utility of anti-Scl-70 autoantibody determinations in the rheumatic diseases. METHODS: Articles from electronic literature searches were retrieved, critiqued and data were extracted and pooled on anti-Scl-70 (topoisomerase I) in relation to history, optimal tests used for its detection, sensitivity, specificity, positive and negative likelihood ratios, indications, interpretation and pitfalls. RESULTS: Anti-Scl 70 antibodies are very useful in distinguishing systemic sclerosis (SSc) patients from healthy controls, from patients with other connective tissue diseases, and from unaffected family members. Among patients with SSc, anti-Scl-70 positivity is useful in predicting those at higher risk for diffuse cutaneous involvement and interstitial fibrosis/restrictive lung disease, though the latter has not been universally observed. Of the four different techniques notably immunodiffusion, immunoblotting, immunoprecipitation and enzyme-linked immunosorbent assay (ELISA) used to assay anti-Scl-70, immunodiffusion has been the most extensively validated. ELISAs are somewhat less specific than other techniques, especially in distinguishing SSc patients from those with other rheumatic diseases, though newer generation ELISAs have been developed to overcome the problem of low specificity inherent with the traditional techniques. As of yet, the need for serial testing of anti-Scl-70 has not been established. CONCLUSIONS: Evidence-based guidelines suggest that anti-Scl-70 antibodies are very useful in the diagnosis and clinical management of SSc patients and also to establish prognosis in these patients, particularly those with diffuse skin involvement.

Antinuclear antibody- and extractable nuclear antigen-related diseases.

In 1948, the observation of the LE cell phenomenon in a patient with systemic lupus erythematosus (SLE) began the discovery of a broad variety of autoantibodies directed to nuclear antigens called antinuclear antibodies (ANA). Nowadays, different ANA serve as important diagnostic parameters for differentiating most of the connective tissue diseases, such as SLE, neonatal lupus syndromes, Sjögren's syndrome, scleroderma, autoimmune myositis, mixed connective tissue disease and other overlaps. This overview summarizes the history of ANA and their detection methods, in part to introduce the subsequent papers dealing with special topics of ANA-related diseases in this issue. Furthermore, the pathogenic role of these autoantibodies in targeting non-organ-specific intracellular antigens as a functional important constituent of a subcellular particle or multimolecular complex is addressed. Notably, some of these autoantibodies have functioned as significant tools for cell biologists to elucidate the subcellular structures and functions of these autoantigens. In the future, we can expect further advances to answer such important questions as why these antigens are targets of autoantibodies, what is their pathogenic impact and what are the triggers of autoimmunity?