Pathology Of Autoimmune Disease

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Hashimoto’s autoimmune thyroidits

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Struma lymphomatosa, Lymphadenoid goiter, and Chronic lymphocytic thyroiditis

Localized Autoimmune disease

4 patients, chronic disorder of the thyroid

diffuse lymphocytic infiltration

thyroid glands of patients:
fibrosis
parenchymal atrophy
eosinophilic change in some of the acinar cells

painless, diffuse enlargement of the thyroid gland in a young or middle-aged woman

associated with hypothyroidism

one of the most common thyroid disorders

inflammation of the thyroid gland

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Normal Thyroid Physiology

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of the thyroid gland contain colloid, the main constituent of which is thyroglobulin

Thyroglobulin is the storage site of the thyroid hormones

Thyroid follicular cells actively take up iodide and attach it to tyrosine residues of thyroglobulin

one iodide is attached to a tyrosine, it results in the formation of monoiodotyrosine (MIT). When two iodides are attached to a tyrosine, it results in the formation of diiodotyrosine (DIT). When two DIT residues couple, thyroxine (T4) is formed. When one MIT residue couples with one DIT residue, triiodothyronine (T3) is formed. Thyroxine and triiodothyronine are cleaved from thyroglobulin before secretion from the thyroid gland. Usually, (T4) secretion predominates

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Clinical presentation of Hashimoto's

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painless enlargement of the thyroid gland or fullness in the throat

-tender goiter, smooth or nodular, firm, and more rubbery than the normal thyroid

many patients have hypothyroidism

symptoms are initially very mild

enlargement of thyroid due to inflammatory cells that destroy thyroid cells, resulting in long term scarring

damaged cells cease thyroid hormone production

Symptoms: fatigue, difficulty concentrating, weight gain, hoarseness, confusion, intolerance to cold, constipation, depression, and hair loss

occasionally patients develop overactive thyroid

Too much thyroid hormone released into the blood stream as thyroid cells are destroyed (short period), followed by normal functioning thyroid

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Hashimoto's Description

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thyroid gland disorder that can occur at any age, but it is most common among middle aged women (incidence increases with age)

onset of the disease is slow

most common cause of primary hypothyroidism in North America

family history of thyroid disorders is common

extensive infiltration of lymphocytes in the thyroid with lymphoid follicles

Late in the disease, the thyroid will be atrophic and smaller than normal

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Laboratory testing for Hashimoto's

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circulating autoantibodies to thyroglobulin and thyroid microsomal antigen (comprised primarily of thyroid peroxidase) measured by immunofluorescence,
agglutination assays, ELISA

present in the serum of more than 90% of patients

thyroid peroxidase antibodies being more common and of higher titer than antithyroglobulin antibodies

patients without serum antibodies, autoantibody production may be localized to the intrathyroidal lymphocytes and plasma cells

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Evaluation of thyroid function

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measure thyroid stimulating hormone (TSH) and thyroxine (T4) levels

Measurement of plasma thyroxine levels is possible, but subject to several confounding variables (only a very small portion of T4 is free)

biologically active amount of thyroid hormone is better reflected as the “Free Thyroxine Index” (FTI), a ratio of T4 to thyroxine-binding globulin

TSH has been found to be a more sensitive indicator of thyroid hormone status

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Elevated TSH

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hypothyroidism

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Elevated TSH with Normal T4

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subclinical hypothyroidism

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Elevated TSH with reduced T4

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true hypothyroidism

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Pathology of Hashimoto's
Gross Appearance

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thyroid enlargement is symmetrical with a conspicuous pyramidal lobe

Tissue is pinkish-tan to frankly yellowish and tends to have a rubbery firmness

capsular surface is gently lobulated and non-adherent to peri-thyroid structures

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Pathology of Hashimoto's
microscopic Appearance

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diffuse process consisting of a combination of epithelial cell destruction, lymphoid cellular infiltration, and fibrosis

thyroid cells slightly larger than normal and have an acidophilic (pink, on an H&E stain) staining character

Hürthle cells and are packed with mitochondria

follicular spaces shrink, and colloid is absent or sparse

Fibrosis ranging from absent to severe

no Foreign body giant cells and granulomas

clusters of macrophage-like cells

lymphoid infiltration in the interstitial tissue is accompanied by actual follicles and germinal centers

Plasma cells are prominent

lymphocytes include equal proportions of T and B cells

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Differential Diagnosis of Hashimoto's

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benign goiters
cancers
other types of thyroditis

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Treatment of Hashimoto's thyroiditis

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lifelong replacement therapy with thyroid hormone to decrease goiter size and treat the hypothyroidism

Occasionally, the hypothyroidism is transient.

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Systemic Autoimmune Diseases

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System Lupus Erythematous (SLE)

Sjögren Syndrome


Systemic Sclerosis (scleroderma)

Rheumatoid Arthritis (RA)

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System Lupus Erythematous (SLE)

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Multisystem disease of autoimmune origin with autoantibodies directed against a broad array of antinuclear antigens (ANA’s), antigens of blood elements and to phospholipid-protein complexes

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SLE Onset

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Acute onset- febrile illness with injury to skin, joints, kidneys and serosal membranes - followed by a chronic phase of remitting and relapsing episodes

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Organs involved in SLE

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Almost any organ may be involved resulting in a variable and complex clinical presentation

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Affected individuals SLE

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SLE is predominately a disease of women (1:700): the female to male ratio 9:1

the disease is more common and severe in American black women (1:245).

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Pathogenesis SLE

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failure of regulatory mechanisms that sustains self-tolerance - resulting in the production of numerous autoantibodies which form immune complexes which, in turn, deposit in blood vessels, kidneys, connective tissues and skin (Type III hypersensitivity)

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Antinuclear antibodies (ANAs)

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(i) antibodies to DNA

(ii) antibodies to histones

(iii) antibodies to non-histone protein bound to RNA

(iv) antibodies to nucleolar antigens

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Indirect Immunofluorescence (IF) test

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patients serum (with autoantibodies) is allowed to react with nuclear antigens of a human epithelial cell line (Hep-2 cells) - a fluorescein conjugated (FITC) antiserum directed against the bound antibodies is added to serve as a marker - the FITC-ANA-Ag complex is then visualized using a fluorescent microscope

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Detection of ANA’s by indirect IF

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(i) homogeneous pattern

(ii) rim or peripheral pattern

(iii) speckled pattern

(iv) nucleolar pattern

(v) centromere pattern

These patterns are not absolutely specific - combinations of patterns are frequent, nonetheless ANA’s are present in virtually every case of SLE thus the test is very sensitive but is not very specific. Approximately 5-15% of normal individuals have low titers of these antibodies.

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homogeneous pattern

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antibodies to chromatin, histones, DNA - “generic” ANA - not specific

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rim or peripheral pattern

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antibodies to double stranded DNA - more specific for SLE

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speckled pattern

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antibodies to non-DNA nuclear constituents extractable in saline - “Extractable Nuclear Antigens or ENA’s (Sm antigen, SS-A,
SS-B, Scl-70) - least specific of the ANA’s

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nucleolar pattern

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antibodies to nucleolar RNA - systemic sclerosis (scleroderma)

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centromere pattern

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CREST syndrome of scleroderma

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detection of antibodies to specific antigens

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more reliable and more specific

1. Anti-double standard DNA (dsDNA) and Sm antigen are diagnostic of SLE

2. Anti-RNP (SS-A, SS-B) - Sjögren’s syndrome

3. Anti-DNA - topoisomerase I (Scl- 70) - systemic sclerosis (scleroderma).

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Autoantibodies developed in SLE

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ANA's

(i) antibodies against red cells, platelets, lymphocytes

(ii) antibodies to proteins complexed to phospholipids

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antibodies to proteins complexed to phospholipids

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present in 40-50% of patients - the proteins include - prothrombin, B2 glycoprotein I, protein S, protein C -- may interfere with in-vitro clotting tests (PTT) - thus referred to as “lupus anticoagulant” - despite “in-vitro” anticoagulant activity, patients with SLE actually have complications results from a “procoagulant” state - vascular thrombosis.

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Pathology of SLE

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The basic mechanism of tissue destruction involves deposition of immune complexes (DNA and anti-DNA) in blood vessels (acute necrotizing vasculitis) in skin, connective tissues, etc. and deposition in the glomeruli of the kidneys (lupus nephritis)

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Pathology of SLE
Skin

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- involved in the majority of patients
- erythematous rash over malar eminences (butterfly pattern) but may also occur on the extremities and trunk
- urticaria, bullae and maculopapular lesions
- light microscopy: liquefactive degeneration of the basal layer of the epidermis
- the dermis exhibits vasculitis and perivascular lymphocytic infiltrates
- immunofluorescence microscopy shows deposition of immunoglobulin and complement along the dermo-epidermal junction

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Pathology of SLE
Kidneys

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- involved in 60-70% of patients by light microscopy however by EM and IF essentially all patients show some abnormality
- lupus nephritis exhibits four basic patterns of glomerulonephritis

(i) mesangial lupus glomerulonephritis (20%)

(ii) focal proliferative (20%)

(iii) diffuse proliferative (40-50%)

(iv) membranous (15%)

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mesangial lupus glomerulonephritis

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(20%) SLE

- mild form - mild hematuria, proteinuria
- mild mesangial thickening - granular deposition by EM/IF

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focal proliferative

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20% SLE

- focal swelling and proliferation of endothelial and mesangial cells, neutrophils, fibrinoid necrosis and capillary thrombi

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diffuse proliferative

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(40-50%) SLE
- most serious of lesions
- proliferation of endothelial, mesangial and epithelial cells
- fibrinoid necrosis, thrombi
- entire glomerulus affected - all glomeruli involved in both kidneys
- microscopic hematuria, nephrotic syndrome

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membranous

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15% SLE

- widespread thickening of capillary walls
- severe proteinuria and nephrotic syndrome

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EM

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electron dense immune complexes that may be mesangial, intramembranous, subepithelial or subendothelial
- all types exhibit mesangial deposits
- membranous type - epithelial
- diffuse proliferative - subendothelial (wire loop)

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Pathology of SLE
Serosal surfaces/pleura/pericardium

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- acute, subacute or chronic inflammation with fibrin deposition

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Pathology of SLE
Other organs

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(i) Heart - non-bacterial verrucous endocarditis (Libman-Sacks) - multiple irregular warty deposits (1-3 mm) on any valve in the heart and on either surface of the leaflets
- increased incidence of coronary atheroscleroses and subsequent risk for MI
(ii) Spleen - onion-skinning of penicilliary arteries - capsular thickening - follicular hyperplasia or white pulp
(iii) Vasculitis may occur in any organ
(iv) CNS - neuropsychiatric manifestations - see changes in small vessels (intimal proliferation due to damage to endothelial cells ). ? role of antibodies directed against a synaptic membrane protein.

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Disease Course of SLE

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1. Variable and unpredictable

2. Flare-ups and remission for years and decades - rare acute disease may lad to death in weeks/months

3. Treatment is usually steroids and/or immunosuppressive drugs

4. 90% 5 yr; 80% 10 yr survival

5. Most common cause of death - renal failure, infections, CNS disease

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Sjögren Syndrome

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Clinicopathologic complex characterized by:
(i) dry eyes - keratoconjunctivitis sicca
(ii) dry mouth - xerostomia
- results from immunologically mediated destruction of lacrimal and salivary glands
- may be primary (“sicca” syndrome) or secondary in cases of RA, SLE, scleroderma

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Pathology Sjogren

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lymphocytic infiltration and fibrosis of lacrimal/salivary glands
by CD4 + helper T cells, some B cells and plasma cells

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Serology Sjogren

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(i) ANA’s in 50-80% of patients

(ii) Rheumatoid factor (RF) in 75% (in absence of rheumatoid arthritis)

(iii) Most specific - antibodies to two RNP antigens - SS-A and SS-B detected in 90% of patients

(iv) Patients with high titers of SS-A tend also to have extraglandular disease (cutaneous vasculitis, nephritis)

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Genetics Sjogrens

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association with HLA alleles (HLA- B8, HLA-DR3, DRW52)

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Pathogenesis Sjogrens

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- despite numerous auto-antibodies there is no direct evidence that they cause tissue injury. As with SLE, the primary offender appears to be CD4 + T helper cells -- ?? Which autoantigen is the dividing force - recent evidence suggest a cytoskeletal protein called alpha-fodrin
- ? role of virus infection as the initiating event (retroviruses).

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Clinical Sjogrens

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(i) approximately 90% of patients are women between ages 35-45 years.

(ii) keratoconjunctivitis - blurring of vision, burning, itching of eyes

(iii) xerostomia - difficulty swallowing, cracks, fissure in mouth, dry mouth

(iv) extra glandular complications - synovitis, pulmonary fibrosis, peripheral neuropathy

(v) Mikulicz disease (syndrome) - lacrimal and salivary enlargement regardless of cause (sarcoidosis, lymphoma, leukemia)

(vi) lymphadenopathy due to follicular (B cell) hyperplasia is not unusual - can predispose to malignant lymphoma (40-fold increased risk)

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Systemic Sclerosis (scleroderma)

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excessive fibrosis throughout the body

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affected areas scleroderma

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The skin is mostly affected but can also see involvement of GI tract, kidneys, heart, muscles, lungs

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Pathogenesis scleroderma

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-antigen - driven activated CD4 + T cells elaborate cytokines and recruit immune cells resulting in the secretion of numerous growth mediators (IL’s, TGF-B, PDGF, etc.) which stimulate fibroblasts to produce collagen.

- in addition, endothelial injury (? granzyme A from CD8+ T cells) results in intimal fibrosis, platelet activation leading to ischemia and fibrosis

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Pathology Scleroderma
skin

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- sclerotic atrophy of skin beginning in the fingers and distal regions of the upper extremities

- edema, perivascular lymphocytes (CD4 + T cells), swelling and degeneration of collagen fibers, thickening and occlusion of small dermal blood vessels, thinning of the epidermis, loss of rete pegs, atrophy of dermal appendages

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Pathology scleroderma
GI tract

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- affected in approximately 90% of patients
- collagenous fibrous replacement of the muscularis especially in the esophagus (stricture, Barrett’s). Loss of villi in small bowel (malabsorption)

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Pathology scleroderma
kidneys

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- 2/3 of patients, most common lesion is fibrosis of blood vessel walls (arteries 150 - 500 um in diameter) - hypertension occurs in 30% of patients.

Renal failure accounts for approximately 50% of deaths.

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Pathology scleroderma
lungs

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50% of patients with pulmonary hypertension and pulmonary fibrosis

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pathology scleroderma
heart

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pericarditis and myocardial fibrosis

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clinical scleroderma

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1. Primarily a disease of women (3:1 ratio)
- peak evidence age 50-60 years

2. Distinctive features - cutaneous changes, Raynaud’s phenomenon, dysphagia, respiratory difficulties, myocardial fibrosis

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Rheumatoid Arthritis (RA)

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Chronic systemic inflammatory autoimmune disorder that principally attacks the joints (arthritis) leading to destruction of articular cartilage and ankylosis (fusion) of the joints.
- can also affect skin, blood vessels, heart, lungs, muscle, etc.
- affects women more than men (3-5:1)
- peak incidence 20's - 40's

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Pathogenesis RA

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-triggered by exposure of an immunogenetically susceptible host to an arthritogenic microbial antigen

- an autoimmune reaction ensues mediated by CD4+ T cells associated with the release of inflammatory mediators (TNF, IL-1, IL-6, IL-5) resulting in inflammation of the synovium, synovial hypertrophy and ultimately joint destruction.

- small joints are affected, especially the small bones of the hands, feet, wrist, ankles, elbows, and knees. Large joints are usually spared.

- involved joints are swollen, warm, painful

- progressive bouts result in marked joint deformity (radial, ulnar deviation).

- about 80% of patients have autoantibodies (IgM) to the Fc portion of autologous IgG - called the rheumatoid factor (RF).

- RF form immune complexes in sera, synovial fluid and synovial membranes.

- Circulating immune complexes underlie most of the extra-articular manifestations of RA.

- RF is not present in some patients with RA, may be present in other autoimmune conditions (without arthritis) and may be

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Pathology RA
joints

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initially the synovium becomes edematous, thickened and hyperplastic, forming papillary fronds

synovium is infiltrated by a dense inflammatory infiltrate of lymphocytes (CD4+ T cells), plasma cells and macrophages.

accompanied by increased synovial vascularity and fibrin deposition within the joint space.

fibrovascular mass called a pannus grows from the synovial lining and extends over the cartilaginous cap of the joint - this pannus erodes the cartilage and eventually fuses the two opposed bones of the joint (ankylosis)

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Pathology RA
skin

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approximately 25% of patients, subcutaneous nodules develop at pressure points (elbow) that represent areas of fibrinoid necrosis of collagen (? ischemic) surrounded by inflammatory cells - called rheumatoid nodules. These nodules may occur in extra-articular sites (lungs, spleen, heart).

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Pathology RA
Blood Vessels

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in some patients with severe disease - - a vasculitic syndrome may develop involving medium to small size arteries resulting in tissue infarction and destruction.