Disorders of the Immune System 3

Richard A. McPherson, M.D.

 Autoimmune Diseases
• Immune reaction against self-antigen
• Range: single organ (cell) disorder to
multisystem
• Connective tissue or collagen vascular disease
• Self-tolerance: no immune response to self
– Clonal deletion: loss of T cell clones during
maturation
– Clonal anergy: inactivation induced by antigens
– Peripheral suppression by T cells
 Mechanisms of Autoimmune
Disease (Loss of self-tolerance)
• Bypass of helper T-cell tolerance
– Modification of molecule-drug complex
– Costimulatory molecules (infection)
• Molecular mimicry
– Microbes share epitopes with self-antigens
– Streptococci and rheumatic heart disease
• Polyclonal lymphocyte activation (Endotoxin, EBV)
• Imbalance of suppressor/helper function
• Emergence of sequestered antigens (e.g., eye, brain)
 Systemic Lupus Erythematosus
Criteria (4 or more)
1. Butterfly rash 7. Neurologic dis
2. Discoid lupus 8. Hematologic dis
3. Photosensitivity 9. Renal disorder
4. Oral ulcers 10. Immunologic dis: LE
5. Arthritis cell, anti-DNA, anti-
6. Serositis Sm, false pos STS
11. Anti-nuclear
antibody
 Systemic Lupus Erythematosus
• Incidence 1:2500
• Female: male 10:1
• 2nd/3rd decade of life
• More common and severe in Blacks
• Skin, kidney, serosal membranes, joints, heart
• Many autoantibodies
• Failure to maintain self-tolerance
Eugenia Zukerman
 Anti-Nuclear Antibodies (ANA)
• Indirect immunofluorescent method
– Hep2 cells + patient serum; + fluor anti-human Ig
• Abs to DNA
• Abs to histone
• Abs to non-histone proteins bound to RNA
• Abs to nucleolar antigens
 Anti-Nuclear Antibody Patterns
• Homogeneous: DNA, histone
• Rim/peripheral: dsDNA
• Speckled: Sm, RNP, SS-A, SS-B
• Nucleolar
• ANA is sensitive
• Pattern is not diagnostic; much overlap between
diseases
• Confirmatory tests are antigen specific
• Abs against RBCs, WBCs, platelets, phospholipids
Homogeneous ANA
Speckled ANA
Nucleolar ANA
Centromere ANA
Monitoring Test: Erythrocyte
Sedimentation Rate
 Systemic Lupus Erythematosus
• Genetic factors
– 30% concordance in monozygotic twins
– Increased risk in family members
– HLA-DQ locus and SLE association
– Inherited deficiency of complement and SLE
• Non-Genetic factors
– Drugs: procainamide, hydralazine
– Sex hormones (estrogens>androgens)\
– UV light
 Systemic Lupus Erythematosus
Morphology
• Acute necrotizing vasculitis
• Skin rash (erythematous/maculopapular)
• Discoid lupus: disc-shaped patches on skin
• Serosa: pericardium, pleura
• Cardiovascular: valvular endocarditis
• Kidney: glomerulonephritis
• Joint: swelling of synovial membranes; bones ok
• Central nervous system: microinfarcts
Glomeruli: subendothelial IC deposits
 Systemic Lupus Erythematosus:
Clinical Course
• Variable
• Flare-ups/ remissions
• Steroids; immunosuppressive drugs
• Renal transplantation
 Rheumatoid Arthritis
• Proliferative synovitis
• Destruction of articular cartilage: disabling
• Extra-articular lesions of skin, heart, blood
vessels, lungs, muscles (similar to SLE, SS)
• Prevalence 1%; starts in 4th/5th decade of life
• Female: male 3-5:1
• Genetic predisposition with microbial initiation
• Rheumatoid factor: anti-IgG Fc
• Juvenile rheumatoid arthritis
Rheumatoid Arthritis:
Proliferative synovitis
Rheumatoid Arthritis
Osteoarthritis

                                                          
James Coburn
James Coburn
 Spondyloarthropathies
• Ligamentous attachments to bone affected
• Sacroiliac joints; uveitis
• Absence of RF
• HLA-B27 association
• Ankylosing spondylitis, Reiter’s syndrome
(urethritis, conjunctivitis)
• Infectious assoc: Yersinia, Shigella,
Salmonella, Helicobacter, Campylobacter
 Case 4
The lifelong concerns of
Norman Cousins                          
(1915-
1990)—writer, editor,
citizen diplomat, promoter
of holistic healing, and
unflagging optimist—
were large indeed: world
peace, world governance,
justice, human freedom,
the human impact on the
environment, and health
and wholeness.
 Norman Cousins
• In the 1960s Cousins had an experience that
changed his life and that, at the same time,
reinforced some of his deepest convictions
concerning the nature of the human being.
Stricken with a crippling and life-threatening
collagen disease, Cousins followed a regimen of
high doses of vitamin C and of positive emotions
(including daily doses of belly laughter), all in
consultation and partnership with his sometimes
skeptical physicians. He chronicled his recovery in
the best-selling Anatomy of an Illness as
Perceived by the Patient: Reflections on Healing
and Regeneration, published in 1979.
 Sjogren’s Syndrome
• Keratoconjunctivitis sicca (dry eyes)
• Xerostomia (dry mouth)
• Immune-mediated destruction of lacrimal and
salivary glands
• Primary: “sicca syndrome” HLA-DR3
• Secondary: with RA, SLE, etc. HLA-DR4
• Women >40 yo
• B cell lymphoma in 1%
• Pseudolymphoma in 10%
 Sjogren’s Syndrome

xerostomia and xerophthalmia

Janine
Turner
 Systemic Sclerosis
• Inflammation /fibrosis of interstitium of organs
• Skin: fingers, upper extremities, shoulders,
neck,face
• GI: esophagus, difficulty swallowing
• Musculoskeletal: joints and muscles
• Lungs: diffuse interstitial fibrosis
• Kidneys, Heart
• Raynaud’s phenomenon: reversible vasospasm
• Limited variant: CREST syndrome
Systemic
Sclerosis
(Scleroderma)
Scleroderma:
Skin patch
Scleroderma: skin thickening
Scleroderma: intense fibrosis
 Other Autoimmune Disorders
• Inflammatory myopathies
– Dermatomyositis
– Polymyositis
• Mixed connective tissue disease
– Features not characteristic of other dis
– Anti-RNP
– Little renal disease
 Immunodeficiencies
• Primary
– X-linked agammaglobulinemia (Bruton)
– Common variable ID (heterogeneous group; M&F)
– Isolated IgA deficiency
– Hyper IgM syndrome
– DiGeorge syn: Thymic hypoplasia
– Severe combined ID
• Secondary
– AIDS
– Lymphatic malignancy
 Laboratory Tests for HIV
• EIA screen for HIV1 and HIV2
• Confirmatory western blot
• RT-PCR qualitative for HIV1
• HIV viral load in serum
• HIV genotype: predicts resistance to drugs
• HIV phenotype: measures resistance to drugs
• CD4 and CD8 counts
 Amyloidosis
• Intercellular pink translucent material on H&E
• Chemical nature: -pleated fibrillar protein
– AL: amyloid light (immunoglobulin) chain
– AA: from serum protein SAA (acute phase reactant)
– Transthyretin
 2-microglobulin
 2-amyloid: Alzheimer’s disease plaques
– Hormones (procalcitonin, proinsulin)
– Inflammation: AL, AA
– Heredofamilial: mutations in transthyretin;
neurological
 Amyloidosis
• Organ deposition
– Kidney, spleen, liver, heart, endocrine
• Diagnosis
– Rectal/gingival biopsy
– Congo red stain
– Serum/urine protein electrophoresis
• Prognosis poor
Protein Electrophoresis: Serum/Urine
Amyloid Deposition in Glomerulus
Congo Red Stain for Amyloid in Kidney
Amyloid Replacing Myocardium
Amyloid in Liver