STEPTRACKERIMMUNOLOGY + RHEUMATOLOGY | AUTOIMMUNITY | HIGH-YIELD REVIEW

Immunologic Features of Systemic Disease

The immune mechanism behind each systemic autoimmune and inflammatory disease — which cell or antibody drives it, how complement behaves and what the tissue shows.

FOCUS ON
SLE: loss of tolerance to nuclear antigens, poor apoptotic-debris clearance, type I IFN signature → types II and III; ↓ C3/C4 in flares; Libman-Sacks endocarditis, lupus nephritis (class IV diffuse proliferative most severe). Sjögren: lymphocytic destruction of salivary/lacrimal glands → dry eyes/mouth; anti-Ro/La; ↑ MALT lymphoma risk. Systemic sclerosis: T cells + TGF-β → fibroblast activation, collagen; vascular injury (Raynaud). Inflammatory myopathies: dermatomyositis (CD4⁺, complement on capillaries, perifascicular atrophy) vs polymyositis (CD8⁺ endomysial). Vasculitides: ANCA (neutrophil activation), immune complex (IgA vasculitis, cryoglobulinemia), granulomatous (giant cell arteritis, Takayasu). Sarcoidosis: Th1 non-caseating granulomas, ↑ ACE, 1α-hydroxylase → ↑ Ca²⁺, CD4:CD8 ratio ↑ in BAL. IgG4-related disease: storiform fibrosis, IgG4 plasma cells.
DISEASE
IMMUNE MECHANISM
TISSUE / LAB FEATURES
CLUE
Systemic lupus erythematosus
Autoantibodies to nuclear antigens; immune complexes (III); cytopenias (II); IFN-α excess
↓ C3, C4; anti-dsDNA; wire-loop lesions (nephritis); Libman-Sacks vegetations; LE cells
Young woman: malar rash, arthritis, serositis, nephritis
Sjögren syndrome
CD4⁺ T and B cells infiltrate exocrine glands
Focal lymphocytic sialadenitis on lip biopsy; anti-Ro/La; RF often ⁺
Dry eyes and mouth, parotid swelling · ↑ B-cell (MALT) lymphoma
Systemic sclerosis
T cells, TGF-β → fibroblasts; endothelial injury
Dermal and visceral fibrosis; anti-Scl-70 or anti-centromere
Raynaud, sclerodactyly, esophageal dysmotility
Dermatomyositis
CD4⁺ T cells, complement-mediated capillary injury
Perifascicular atrophy, perimysial inflammation; ↑ CK
Heliotrope rash, Gottron papules · screen for cancer
Polymyositis
CD8⁺ T cells attack muscle fibers (MHC I up)
Endomysial infiltrate; ↑ CK; anti-Jo-1
Proximal weakness, no rash
Rheumatoid arthritis
CD4⁺ Th1/Th17, B cells, TNF-α, IL-6 → synovial pannus
RF, anti-CCP (citrullinated proteins; smoking)
HLA-DR4 · TNF and IL-6 blockers, abatacept, rituximab
ANCA vasculitis
ANCA activates primed neutrophils → small-vessel necrosis
Pauci-immune (few deposits) GN; granulomas in GPA and EGPA
Cyclophosphamide or rituximab + steroids
IgA vasculitis (Henoch-Schönlein)
IgA immune complexes in small vessels
IgA deposits in skin and mesangium
Child after URI: purpura on legs, arthralgia, abdominal pain, nephritis
Giant cell arteritis · Takayasu
Th1/Th17 granulomatous inflammation of large arteries
Granulomas with giant cells; ↑ ESR, IL-6
GCA > 50 (temporal headache, jaw claudication) · Takayasu < 40 (pulseless) · tocilizumab
Sarcoidosis
Th1 response to unknown antigen → non-caseating granulomas
↑ ACE, hypercalcemia (macrophage 1α-hydroxylase), CD4:CD8 > 3.5 in BAL; cutaneous anergy
Bilateral hilar adenopathy, erythema nodosum, uveitis
IgG4-related disease
IgG4 plasma cells, Th2/Tfh, fibrosis
Storiform fibrosis, obliterative phlebitis; ↑ serum IgG4
Autoimmune pancreatitis, Riedel thyroiditis, retroperitoneal fibrosis · steroids
Spondyloarthropathies
HLA-B27, IL-17/IL-23 axis
Enthesitis, sacroiliitis; seronegative (RF −)
Ankylosing spondylitis, psoriatic, reactive, IBD-associated · IL-17 blockers

Mechanism — why lupus targets nuclei

Apoptotic debris not clearedEarly complement ↓, defective DNase
→
Nuclear antigens activate TLR7/9pDCs make IFN-α
→
Autoreactive B cells → anti-nuclear IgG
→
Immune complexes → nephritis, skin, joints

Myositis compared

FEATURE
DERMATOMYOSITIS
POLYMYOSITIS
Effector
CD4⁺, complement
CD8⁺ T cells
Location
Perimysial, perifascicular
Endomysial
Skin
Heliotrope, Gottron
None
Cancer link
Strong
Weaker

How it's tested

COMMON CONFUSIONGranulomas: sarcoidosis (non-caseating, ↑ ACE, ↑ Ca²⁺) vs TB (caseating) vs GPA (necrotizing granulomas with vasculitis, PR3-ANCA).
THE TRAPLow complement points to immune-complex disease (SLE, cryoglobulinemia); ANCA vasculitis is "pauci-immune" with normal complement.
YOUR APPROACHClinical syndrome → effector (antibody, complexes, CD4, CD8, granuloma) → tissue and lab marker → targeted therapy.

If you see… think…

Wire-loop glomeruli, low C3/C4, anti-dsDNA → lupus nephritis
Dry eyes, dry mouth, parotid swelling, later lymphoma → Sjögren (MALT)
Heliotrope rash with perifascicular atrophy → dermatomyositis
CD8⁺ endomysial infiltrate, proximal weakness → polymyositis
Non-caseating granulomas, hypercalcemia, ↑ ACE → sarcoidosis
Child with leg purpura, abdominal pain and hematuria after a cold → IgA vasculitis
Pancreatic mass with storiform fibrosis and ↑ IgG4 → IgG4-related disease
Jaw claudication, ↑ ESR in an older adult → giant cell arteritis
Pauci-immune crescentic GN with p-ANCA → microscopic polyangiitis
HLA-B27 with enthesitis, RF negative → spondyloarthropathy