Immunopathological events initiated and maintained by pathogenic IgG autoantibodies in an experimental autoimmune kidney disease

Abstract

The experimental models of Heymann nephritis (HN) and slowly progressive Heymann nephritis (SPHN) give us rare opportunities to investigate the etiologies and pathogenesis of two immunopathological processes in rats leading to: (1) autoimmune disease, where the autoimmune disease HN and SPHN is initiated and maintained by cross-reactive pathogenic IgG autoantibodies (aabs) directed against the renal proximal convoluted tubules' brush border (BB) cells - where the nephritogenic antigen (ag) is produced and localized - damaging and releasing BB associated nephritogenic ag into the circulation which in turn contributes to continuation of the autoimmune disease; and (2) immune complex glomerulonephritis, where the glomerular injury is initiated, proceeding into a chronic progressive disease by depositing immune complexes (ICs) - made up of a glomerular epithelial cell produced endogenous nephritogenic ag and the developing pathogenic IgG aab directed against the nephritogenic ag, and complement components - on the epithelial side of the glomerular basement membrane. We also observed how the normally functioning immune system is able to avert autoimmune disease developments by circulating specific non-pathogenic IgM aabs clearing the system of intracytoplasmic ags released from cells at the end of their life spans or following damage by toxic agents. We also described how an autoimmune disease SPHN can be prevented and when present terminated by the implementation of a new vaccination technique we have developed and call modified vaccination technique. By increasing the specific IgM aab production against the native nephritogenic ag - by injecting ICs made up of: [nephritogenic ag X homologous anti-nephritogenic ag IgM ab] in slight ag excess into SPHN rats - pathogenic IgG aab producing native and modified nephritogenic ags were removed from the circulation and termination of the autoimmune disease causing immune events was achieved. Even though HN and SPHN are not well-known disease models, their studies are important because the etiologies and pathogenesis of two conditions - that can also occur in humans, namely autoimmune diseases and membranous glomerulonephritis - can be simultaneously investigated.

Impact of IgG Fc-fragments on experimental glomerulonephritis induced by <i>Streptococcus pyogenes</i> strain binding various immunoglobulin classes

“…Согласно литературным данным и более ранним нашим [4,8,9] исследованиям, постстрептококковый гломерулонефрит известен как мембранозно-пролиферативный процесс, первично проявляющийся отложением IgG или IgG-anti-IgG иммунных комплексов в базальной мембране клубочков [4,9,21], между тем как для IgA-нефропатии свойственны отложения IgA или его полимеров в мезангиальных клетках клубочков, ведущие к мезангиальнопролиферативному гломерулонефриту [3,18,19,20,24]. За этими проявлениями фактически должно стоять реальное распределение соответствующих Fc-рецепторов в структурах гломерул.…”

Modified self-antigen Caused Autoimmune Disease and its Reversal by a new Vaccination Technique

“…We have shown that only modified nephritogenic ags, injected into rats in adjuvants [6,7] or in a chemically modified state [3], can induce the production of pathogenic IgG aabs which are responsible for the autoimmune kidney disease after coming into contact with and damaging the BB region of the renal proximal convoluted tubules [27,45] where the nephritogenic ag resides (primary insult to the kidney causing the autoimmune kidney disease. )…”

“…The secondary insult to the kidney's glomeruli -by the developing pathogenic IgG aabs, directed against the nephritogenic ag -starts by the pathogenic IgG aabs reacting with free antigenic sites of the IC [nephritogenic ag X rat anti-rat nephritogenic ag non-pathogenic IgM aab] containing nephritogenic ags [26,33,45]. The insult continues as layered deposition of ICs form on the epithelial side of the GBM in the presence of complement composed of: the continually released nephritogenic ag from the renal proximal convoluted tubules and the pathogenic IgG aab directed against the nephritogenic ag [18,50].…”

NEPHRITOGENIC ACTIVITY OF STREPTOCOCCUS PYOGENES emm1 AND emm12 GENOTYPES ISOLATED FROM PATIENTS AND ASYMPTOMATIC CARRIERS

“…При этом рецептором для них скорее всего должен слу-жить Mrp-белок, а не Emm-белок, поскольку последний обычно связывает все подклассы IgG, включая IgG3. Ранее было показано, что Mrp-белок является более слабым индуктором экспериментального PSGN в сравнении с Emm-белком [3].…”

“…Потеря молекулами IgG чувствительности к перевариванию энзимами указывает на приобретение ими новой струк-туры, приводящей к индукции анти-IgG анти-тел. Это допущение согласуется с недавними представлениями об участии патогенных IgG антител в генезе аутоиммунного гломеруло-нефрита [3].…”