Module 5 · Visual Grammar

Immune Deposition and Pathogenesis

LM shows tissue response. IF identifies the reactant and pattern. EM localizes deposits. The diagnosis is the synthesis.

Before you pick an entity, categorize the pathogenesis

Pathogenesis

LM pattern: Variable: mesangial or endocapillary hypercellularity, MPGN pattern, membranous pattern, or crescents.
IF pattern: Granular immune-reactant staining — mesangial and/or capillary wall — with IgG, IgA, IgM, C3, ± C1q.
EM findings: Electron-dense deposits in mesangial, subendothelial, subepithelial, and/or intramembranous locations depending on entity.
Clinical correlation: Lupus, IgA nephropathy, post-infectious GN, membranous nephropathy, cryoglobulinemic GN, hepatitis-associated GN.
Common pitfalls: Do not equate 'granular IF' with any single disease — location and reactant combination narrow the differential.

Quick check

Full-house IF staining (IgG, IgA, IgM, C3, C1q) with subendothelial deposits on EM is characteristic of:

Pathogenesis

LM pattern: Necrotizing and/or crescentic GN, often segmental.
IF pattern: Scant or absent immune reactant staining ('pauci-immune').
EM findings: No significant electron-dense deposits.
Clinical correlation: ANCA-associated vasculitis (MPA, GPA, EGPA); RPGN.
Common pitfalls: Pauci-immune does not mean no inflammation — the LM injury is severe. Correlate with ANCA serology.

Quick check

A crescentic GN with pauci-immune IF and MPO-ANCA positivity is most consistent with:

Pathogenesis

LM pattern: Necrotizing/crescentic GN, often with all crescents at similar stage.
IF pattern: LINEAR IgG (± C3) along the GBM.
EM findings: No discrete electron-dense deposits.
Clinical correlation: Anti-GBM antibody-mediated RPGN, ± pulmonary hemorrhage (Goodpasture).
Common pitfalls: Diabetic and monoclonal Ig deposition disease can produce pseudo-linear IgG; correlate with serology.

Quick check

Linear IgG along the GBM by IF, with cellular crescents and no EM deposits, points to:

Pathogenesis

LM pattern: MPGN pattern, membranous-like pattern, proliferative GN with monoclonal Ig deposits (PGNMID), or organized deposits (immunotactoid, cryoglobulinemic).
IF pattern: Light-chain–restricted (kappa OR lambda), often with a single IgG subclass (e.g. IgG3-kappa in PGNMID).
EM findings: Granular, fibrillar, microtubular, or crystalline deposits depending on entity.
Clinical correlation: Monoclonal gammopathy of renal significance (MGRS), myeloma, Waldenström, chronic lymphocytic disorders.
Common pitfalls: A monoclonal serum spike is not required — negative SPEP/UPEP does not exclude MGRS.

Quick check

Proliferative GN with granular capillary-wall IgG3-kappa on IF and non-organized deposits on EM fits:

Pathogenesis

LM pattern: MPGN pattern most commonly; may be mesangial or endocapillary proliferative.
IF pattern: C3-dominant staining (C3 ≥2 orders of magnitude greater than any Ig).
EM findings: C3 glomerulonephritis: mesangial/subendothelial deposits. Dense deposit disease: highly osmiophilic intramembranous deposits.
Clinical correlation: Alternative complement pathway dysregulation; low C3, normal C4 typically.
Common pitfalls: Post-infectious GN can look C3-dominant during resolution — persistent C3-dominance beyond weeks argues for C3G.

Quick check

C3-dominant IF with highly electron-dense intramembranous deposits defines: