Disease Caused by Antibodies Directed Against Normal Components of the Glomerular

Basement Membrane
In anti-GBM antibody induced glomerulonephritis,
antibodies bind to intrinsic antigens homogeneously
distributed along the entire length of the GBM,
resulting in a diffuse linear pattern of staining for
the antibodies by immunofluorescence techniques.
These intrinsic, fixed antigens cannot be mobilized to
form large, discrete complexes.
The anti-GBM antibodies cross-react with other basement membranes, especially those in
the lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture
syndrome).
The GBM antigen that is responsible for classic anti-GBM antibody-induced
glomerulonephritis and Goodpasture syndrome is a component of the noncollagenous
domain (NC1) of the α-3 chain of type IV collagen that is critical for maintenance of GBM
supra structure.
 FREQUENCY: - < 5% of cases
 SYMPTOMS: -severe necrotizing and crescentic glomerular damage
 RPGN.
Glomerulonephritis Resulting from Deposition of Circulating Immune Complexes
 glomerular injury is caused by the trapping of circulating Ag-Ab complexes within
glomeruli.
 The antibodies have no immunologic specificity for glomerular constituents, and
the complexes localize within the glomeruli because of their physicochemical properties
and the hemodynamic factors peculiar to the glomerulus.
 The antigens that trigger the formation of circulating immune complexes may be:-
o Endogenous origin :-glomerulonephritis associated with SLE
in IgA nephropathy
o Exogenous origin:- certain infections
bacterial products (streptococcal proteins),
surface antigen of hepatitis B virus, hepatitis C virus antigens,
and antigens of Treponema pallidum, Plasmodium falciparum.
The inciting event underlying the glomerulonephritis is deposition of the antigens with
subsequent formation of immune complexes in situ rather than deposition of
preformed immune complexes from the circulation.

Deposition of circulating immune complexes in the glomerulus

initiates complement (and/or Fc receptor) mediated leukocyte activation

glomerular injury The localization of antigen, antibody, or immune

complexes determines the glomerular injury response.

Morphologically, affected glomeruli exhibit

leukocytic infiltrates and variable proliferation
of mesangial and parietal epithelial cells.
Electron microscopy reveals electron-dense immune deposits in one or more of three
locations:
subendothelial deposits:-between the endothelial cells and the GBM
elicit an inflammatory reaction in the glomerulus with infltration of leukocytes and exuberant
proliferation of glomerular resident cells
subepithelial deposits:-between the outer surface of the GBM and the podocytes
, antibodies directed to the subepithelial region of glomerular capillaries are often
noninflammatory, as seen in primary membranous nephropathy
mesangial deposits.
The pattern of immune complex deposition by immunofluorescence microscopy is
granular, given the rather picturesque description of “lumpy-bumpy” by pathologists
Once deposited in the kidney, immune complexes may eventually be cleared by degradation or
phagocytosis, mostly by infiltrating leukocytes and mesangial cells.
FATE OF INFLAMMATORY REACTION:-
Subside if the exposure to the if exposure to antigen is sustained, repeated cycles of
inciting antigen is short-lived and immune complex formation, deposition, and injury
limited, as in most cases of occur, leading to chronic GN.
poststreptococcal or acute
hepatitis B virus infection
infection–related GN.
self-nuclear antigens in systemic lupus erythematosus

Although immune complex deposition is a common mechanism of injury, circulating complexes

are almost never identified in human disease, likely because of technical limitations.

Minimal-Change Disease/lipoid nephrosis

 Relatively benign disorder
 Characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes), detectable only by E/M.
 MOST COMMON cause of nephrotic syndrome in children
 The peak incidence is between 2 and 6 years of age.
 The disease sometimes follows a respiratory infection or routine prophylactic immunization.
 Etiology and Pathogenesis.
Pathology has an immunological basis supported by:-
→ the clinical association with respiratory infections and prophylactic immunization
→ respond to corticosteroids and/or other immunosuppressive therapy
→ the association with other atopic disorders (e.g., eczema, rhinitis)
→ increased prevalence of certain HLA haplotypes (suggesting a genetic predisposition)
→ the increased incidence in patients with Hodgkin lymphoma
 Immune dysfunction results in the elaboration of factors that damage visceral epithelial cells and cause proteinuria
For EXAMPLE:-Angiopoietin-like-4
 The ultrastructural changes point to a primary visceral epithelial cell injury (podocytopathy), suggesting the loss of glomerular
polyanions.
Thus, defects in the charge barrier may contribute to the proteinuria.
 The actual route by which protein traverses, include following possibilities:-
→ transcellular passage through the epithelial cells
→ through residual spaces between remaining but damaged foot processes
→ through abnormal spaces developing underneath the portion of the foot process that directly abuts the basement membrane
→ leakage through foci in which the epithelial cells have become detached from the basement.
 MORPHOLOGY
→ The glomeruli are normal by light microscopy
→ Immunofluorescence studies show no Ig or complement deposits.
→ By electron microscopy the GBM appears normal, and no electron dense material is deposited.
→ The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes,
→ Foot process reduced to a rim of cytoplasm with loss of recognizable intervening slit
→ It represents simplification of the epithelial cell architecture with flattening, retraction, and swelling of foot processes.
→ Foot process effacement when effacement is associated with normal glomeruli by light microscopy that the diagnosis of minimal-
change disease can be made.
→ proximal tubule cells are often laden with lipid and protein, reflecting tubular reabsorption of lipoproteins passing through diseased
glomeruli
 Clinical Features
→ massive proteinuria
→ The proteinuria usually is highly selective, most of the protein being albumin
→ no hypertension or hematuria.
 PROGNOSIS:-
→ prognosis for patients is excellent,
→ Most children (>90%) with minimal-change disease respond rapidly to this treatment
→ A characteristic feature is its usually dramatic response to corticosteroid therapy.
→ Proteinuria may recur, and some patients may become steroid-dependent or resistant
→ Although adults are slower to respond, their longterm prognosis is also excellent.