Immunopathology Part 2
AUTOIMMUNE DISEASES
• Localized (Hashimoto thyroiditis)one organ
• Generalized (Systemic Lupus Erythematosus) systemic
• Selective (Goodpasture Syndrome) lung and kidney
SLE: GENERAL (systemic lupus erythmatosis)
• Prevalence: 1 in 2,500. Female >> male (9:1), beginning age 20-30
• Pathogenesis: failure of self-tolerance
u damage caused by CD4-driven, B-cell response to self-antigens
LE test: antibodies to the nuclei of
lymphocytes. Cells have to be busted. LE
• Immunology:
cell= Big blue blobs. NOT used anymore!
u ANAs: antinuclear antibodies:
double-stranded DNA, RNP(ribonucleo protein) (Smith), histones, nucleoli
– antiphospholipid antibody syndrome (paradoxical)
– Type III hypersensitivity >> Type II (warm hemolytic a)
– LE cells/bodies spontaneous or not
• Genetic factors:
u antibodies in  20% of well, 1st degree relatives
indirect FANA - fluorescent antiu concordance in >20% in monozygotic twins
nuclear antibody. This is used!
– < 3% in dizygotic twins
Antigen is in nucleus- dsDNA. Rim
is seen in lupus
u specific alleles of HLA-DQ involved in antibodies
u in 6%, deficiencies of Clq, C2, C4
– impairs removal of complexes by MØs
during flare-ups, may be hypocomplementemia Why?- consumption and deposition (type III)
• Miscellaneous factors:
u environmental: hydralazine, isoniazid, others
u UV:
–
u
keratinocytes produce IL-1
– alters self-DNA to become immunogenic
sex hormones: SLE may be worse
– in pregnancy
– during menses
kidney: vasculitis; focal glomerulo
nephritis; C’. proliferation.
liquefaction necrosis in skin.
Hemosiderin.antibodies present
SLE: PATHOLOGY
• BVs: acute necrotizing vasculitis. Fibrinoid. Skin, muscle, spleen
• Kidney: DNA, anti-DNA, Ig, C dep. in glomeruli, capillary & tubular b.m.’s
• Skin: butterfly lesions. Immunofluorescence along DE jnx, beyond
• Joints: pmns, fibrin in synovium. Perivascular mononuclears.
• CNS: non-inflammatory intimal proliferation ± occlusion, infarcts.
• Serosa (incl. pericardium): acute, subacute, chronic.
u fibrinous component may lead to fibrous obliteration
• Heart: Libman-Sacks, intramural inflammation, accelerated athero.
• Spleen: onion-skinning; plasma cells
Camel humps outside
endocarditis
with vegitation
on either side of
valve – libman
sacks
entothelium
lymph node
(ss). Necrosis, anti-nuclear abs
wire loop glomerulus; deposition of immune
complexes on BM. Subendothelial.
CHRONIC DISCOID LUPUS ERYTHEMATOSUS
• For the most part: skin only
u late in disease may become systemic (5-10%)
• Face and scalp
• (+) ANA in 35%, rarely to double-stranded DNA
• Immunofluorescence along DE junction
u but generally not beyond lesion
DRUG-INDUCED LUPUS ERYTHEMATOSUS
• 46 agents: hydralazine (BP), isoniazid (TB), procainamide*
• Most have ANAs but do not have Sx of SLE
• Arthalgias, fever, serositis
• No renal or CNS involvement
• High frequency of antihistone abys (>95%)
• HLA-DR4 predisposes to reaction from hydralazine
• Relents following withdrawal of drug
• *Given for arrhythmias; 80% have ANAs
SJÖGREN SYNDROME: CLINICAL
• Mostly women (90%), aged 40-60
• Immune-mediated destruction of exocrine glands
u lacrimal glands
u salivary glands (involved in 50% of cases)
u ± respiratory glands (± GI, ± vagina)
• In 33%, extraglandular disease:
u synovitis
u pulmonary fibrosis
u peripheral neuropathy
• in 60%, other immune disorder, e.g.
u RA (Rh factor present in 75% of patients)
• Definition of Mikuklicz (lacrimal and salivary) syndrome
• Diagnosis is by
u
lip biopsy (why? Lacrimal and salivary glands are not good to biopsy
and there are mucus glands in lip)
u high titers of abys to RNP agns: SS-A, SS-B
• present in 60-95%
• ribonucleoprotein (non-DNA)
u high frequency of lymphoma (40-fold increase)
• mostly extranodal e, in GIT
SJÖGREN SYNDROME: IMMUNOPATHOLOGY
• Anti-ribonucleoprotein (anti SS-A, SS-B) in 60-95%
u If anti SS-A titers high: lung, kidney, skin, CNS involved
– early onset, longer duration
– rheumatoid factor present in 75% of patients
• Respiratory tract: ulcerations  bronchitis, bronchiolitis
• Kidneys: tubulointerstitial nephritis
u mononuclears x3 with renal tubular acidosis
speckled pattern
Smith Antigen: positivity is also speckled
(=SLE)
Nuclear RNP positivity is speckled (=MCTD,
SLE)
SS-A positivity may be speckled or neg. (-low
titer)
Sjorgren syndrome or SLE
SS-B positivity is speckled in Sjorgen
syndrome
•
u glomerular lesions extremely rare
Salivary glands: in arena, CD4+, some B cells, plasma cells
u early, infiltrate is periductal, perivascular
– may contain germinal centers (think benign)
u ductal lining cell hyperplasia may lead to obstruction with
– acinar atrophy
– fibrosis, hyalinization
– fatty replacement
WHAT CAUSES SJÖGREN SYNDROME?
• No evidence that high titers of abys cause it
• Most likely CD4+ T-cells are responsible
u some have expanded clonally
u still, their target antigen is unknown
u one possibility is -fodrin
– a cytoskeletal protein
• Possible roles of viruses
salivary gland full of lymphocytes; ducts are
obliterated. Fat coming in.
SCLERODERMA: GENERAL STATS
• Synonym: systemic sclerosis (SS)
• Females 3:1 over males
• 50-60 years of age
• Excessive collagen (I, II, III) deposition, body-wide at outset
u Occasionally confined to skin
• 1º vs 2º Raynaud phenomenon
u 1º benign. Prevalence 2-3%.
u 2º in 100% of SS. Sx precedes SS in 70%.
SCLERODERMA: VARIANTS
• Diffuse: skin most common site
u multiorgan
u rapid progression
• Limited: fingers, forearm, face (FFF)
u visceral involvement late; benign
u CREST in some (see later)
duct with hyperplasia…no lumen
•
u
•
u
•
u
SCLERODERMA (SS): IMMUNOPATHOLOGY
• Unknown agn. in skin attracts oligoclonal CD4+ T-cells
u T-cells release cytokines to recruit mast cells & MΦs
u trio releases shower of mediators, e.g. TGF-b, PDGF
u these upregulate genes in fibroblasts, which make
collagen and tissue fibronectin
• Concomitant microvascular disease
u intimal fibrosis in digital arteries
u endothelial injury (by granzyme A?), evidenced by
–  von Wf, plt. activation ( % of plt. aggs in PB)
u release of platelet factors (PDGF, TGF-b) causing
– periadventitial fibrosis
SCLERODERMA (SS):
IMMUNOPATHOLOGY: OVERVIEW
Unknown antigen stimulates CD4+ T-cells
produce cytokines
Microvascular injury
e.g., nail-bed capillaries
Humoral activity
ANA antibody to DNA topoisomerase I
nucleolar FANA in SS
•
•
•
u end-point: ischemic injury
Parallel humoral activity, e.g., anti-Scl 70
Humoral activity (ANAs)
u anti-DNA topoisomerase I (Scl-70)
– 30-70% of patients with diffuse SS
– highly specific
When Scl-70 is present, patients likely to have
u pulmonary fibrosis
u peripheral vascular disease
SCLERODERMA (SS): PATHOLOGY
• Skin: thickening, from fingers cephalad
u moves from “talons” cephalad to face (mask)
u edema, perivascular lymphocytes, fibrosis
u bvs partially occluded
u dense dermal collagen, ± autoamputation
• GI tract:
u dysphagia due to “rubber hose” esophagus (lower 2/3)
u collagenosis. Ulcers. Loss of villi  malabsorption
• Joints: inflammation, synovial hyperplasia, fibrosis*
• Kidneys: interlobular arteries (150-500 mm)
u 50% go into renal failure (mild proteinuria in 70%)
u hypertension in 30% (malignant in 20%)
• Lungs: diffuse interstitial fibrosis (50%)
u major cause of death
u ± pulmonary hypertension (consequences ?)
• Heart: myocardial fibrosis ± failure
u arrhythmias (AV node involved)
u pericarditis with effusions
CREST SYNDROME
• Subset of limited SS (largely confined to skin)
• Visceral involvement late (therefore rel. benign)
• Anticentromeric antibodies:
u in 90% of patients with CREST
u in 22-36% of patients with SS
u What is CREST?
SUMMARY OF RELATIVELY SPECIFIC ANAS
• Anti-double-stranded DNA: SLE (40-60%)
• Anti-Smith (small ribonucleoprotein particles): SLE (20-30%)
• Antihistone: drug-induced SLE (>95%)
• Antiribonucleoprotein (SS-A, SS-B): Sjogren’s syndrome (70-90%)
• Anti-DNA topoisomerase 1 (Scl-70): Scleroderma (30-70%)
• Anticentromeric proteins: CREST (90%)
FREQUENCY OF POSITIVE ANAs
SLE
90-100%
Sjogren Syndrome
50-85%
Scleroderma
88%
POLYARTERITIS NODOSA (PAN)
• Young adults, male > female
• Ill-defined immune-mediated vasculitis with fibrinoid necrosis
u hepatitis B antigen in 30%
• Small or medium-sized muscular arteries only
u predilection for bifurcation points
u ± aneurysms
u thrombosis, ischemia, infarction, hemorrhages
• Kidneys > heart > liver > GIT > CNS > skin. NOT LUNG.
• No ANCAs
• Staging: acute, healing, healed
u multistage at any one point in time
• S + Sx:
u fever, hematuria*, uremia,  BP, melena, motor neuritis
• : angiography (aneurysms), skin or kidney biopsy
• Prognosis with steroids / cyclophosphamide
u 90% remissions / cures
* Not caused by glomerulonephritis! Why?
Small or medium artery necrosis
HYPERSENSITIVITY (LEUKOCYTOCLASTIC) ANGIITIS
• Necrotizing vasculitis
• Smaller vessels than PAN (“microscopic polyarteritis”)
u arterioles, capillaries, venules
• Widespread, including skin, kidneys, lungs, joints. Sx?
• All lesions at same stage of development (cf with PAN)
• Immunogen often traceable
u penicillin, strep., heterologous proteins, tumor agns
• Igs and C´ often present in lesions in acute phase
u rarely found in developed disease
• Pathology:
u ± fibrinoid necrosis of media
u no infarcts (why?)**
u leukocytoclasia mostly involves post-capillary venules
• May complicate other diseases including collagen vascular
• Usually relents with removal of immunogen
• How does distribution differ from PAN?
u lungs and glomeruli involved
• p-ANCA present in 70% (what is ANCA?)
AMYLOIDOSIS:
•
•
PROPERTIES/Subsets
Paired fibrils (95%), b cross-pleated
Binding sites for Congo red.
• AL ( > k). Full or partial molecules of light chains
• amyloidosis: primary or secondary to MM ( = rare )
• AA (from SAA). 76 a.a. residues
• RA, CUC, Crohn’s, subcutaneous heroin
• transthyretin (pre-albumin), normal variant
• deposited in heart* in senile systemic amyloidosis
AMYLOIDOSIS AA: ORIGINS
• Acute phase reaction:hypersynthesis in liver:
u CRP*, fibrinogen*, SAA (x100s)
u upregulation by IL-6* and IL-1
• CRP & SAA: may act as opsonins for bacteria
• CRP: marker for increased risk of MI (how?)
• SAA: prolonged production  AA amyloidosis
AMYLOID IN PNS
Infiltration of carpal tunnel may
damage
u median nerve with
consequent
u atrophy of hand muscles
•
AMYLOIDOSIS: DISTRIBUTION
1° Immunocytic (AL)
u Heart
u GI tract
u PNS
u Skin
u Tongue
u Kidney
Immunocytic dyscrasia
2° Reactive (AA)
u Kidneys
u Liver
u Spleen
u LN
u Adrenals
u Thyroid
Reactive systemic
AMYLOIDOSIS: DIAGNOSIS
• Biopsies
u kidney
u gingiva
u rectum
u bone marrow
• Abdominal fat-pad aspirates
u specific but low sensitivity
AMYLOIDOSIS: PROPERTIES / SUBSETS (2)
u b2-microglobulin (component of MHC class I):
u membrane retention during long-term hemodialysis
u synovium, tendon sheaths, joints (carpal tunnel syndrome)
u Endocrine:
u medullary carcinoma of thyroid (polypeptide hormones)
u islets of diabetes mellitus II (islet polypeptides)
u b-amyloid protein (Ab) in
u Alzheimer plaques
u cerebral blood vessels
AMYLOIDOSIS: ORGAN PATHOLOGY
• Kidney: gloms (mesangium, b.m.), intersitium, bvs
• Spleen: (early) perifollicular. “Sago” vs “lardaceous.”
• Liver: space of Disse, bvs. Normal liver function. Bx?
• Heart: endocardial dewdrops, bvs walls, myocardium*
• Adrenals: (early) ZG. Later ZF, ZR
• GI tract: perivascular. Later  SM, M, serosa
• Tongue: macroglossia (nodular deposits)
• CNS: plaques + bvs of Alzheimer disease
*CHF, arrhythmias, cardiomyopathy, constrictive pericarditis.
AMYLOIDOSIS:
•
•
•
CLINICAL CORRELATES
Renal: proteinuria  renal failure
Cardiac: A-V conduction system  failure
Tongue: impaired speech, swallowing