A specific antibody and epitope binding that shows the highest affinity and is pathogenic occurs between GPA antibodies and the anti-GBM epitope region, designated EA, which is residues 17-31 of the alpha 3 subunit of non-collagenous domain of type IV collagen. T cells are also implicated, though it is generally considered a type II hypersensitivity reaction. Diagnosis
The diagnosis of GPS is often difficult, as numerous other diseases can cause the various manifestations of the condition and the condition itself is rare. The most accurate means of achieving the diagnosis is testing the affected tissues by means of a biopsy, especially the kidney, as it is the best-studied organ for obtaining a sample for the presence of anti-GBM antibodies. On top of the anti-GBM antibodies implicated in the disease, about one in three of those affected also has cytoplasmic antineutrophilic antibodies in their bloodstream, which often predates the anti-GBM antibodies by about a few months or even years. The later the disease is diagnosed, the worse the outcome is for the affected person.In addition, if there is substantial suspicion of the disease, seralogic testing for ELISA assay is usually done by looking for alpha3 NC1 domain area of collagen IV in order to avoid false positives. Treatment
The major mainstay of treatment for GPS is plasmapheresis, a procedure in which the affected persons blood is sent through a centrifuge and the various components separated based on weight. The plasma contains the anti-GBM antibodies that attack the affected persons lungs and kidneys, and is filtered out.
Cause
While the exact cause is unknown, the genetic predisposition to GPS involves the human leukocyte antigen (HLA) system, specifically HLA-DR15. In addition to genetic susceptibility, an initial environmental insult to the pulmonary vasculature is needed to allow the anti-glomerular basement membrane (anti-GBM) antibodies to reach the alveolar capillaries. Examples of such an insult include: exposure to organic solvents (e.g. chloroform) or hydrocarbons, exposure to tobacco smoke, infection (such as influenza A), cocaine inhalation, metal dust inhalation, bacteremia, sepsis, high-oxygen environments, and antilymphocyte therapies (especially with monoclonal antibodies). Exposure to dry cleaning chemicals and Paraquat brand weed killer have also been implicated as potential insults. In GPS, anti-GBM antibodies are produced and circulated throughout the bloodstream, damaging the membranes lining the lungs and kidneys as well as targeting their capillaries. Pathophysiology
GPS is caused by abnormal plasma cell production of anti-GBM antibodies. The major target of these abnormal antibodies is the non-collagen domain of the alpha-3 chain of type 4 collagen, which is mostly found in the basal membranes of glomerular and alveolar capillaries, explaining the obscurely specific symptoms of this condition. This preferred targeting of these alpha-3 collagen chains specifically in the basal membranes of glomerular and alveolar capillaries can be explained by the higher accessible exposure of epitopes, a larger expansion of the alpha-3 collagen units, and because these alpha-3 collagen chains structurally provide higher accessibility for the targeting antibodies. These antibodies bind their reactive epitopes to the basement membranes and activate the complement cascade, leading to the death of tagged cells.