Chapter 6 part (Dr. Guervin) TEST 2 Flashcards
Autoimmune Diseases
• Affect at least 1-2% of the US population; Women»_space;> Men
• Presence of AUTOANTIBODIES ≠ AUTOIMMUNE Disease
– Autoantibodies can be found in normal individuals (more common as we age)
– Autoantibodies can be produced after damage to tissues
• Pathologic Autoimmunity “CONFIRMED” when:
– Presence of an immune reaction specific for some Self Antigen or Self Tissue
– Evidence that such a reaction is NOT Secondary to tissue damage but is of PRIMARY Pathogenic significance
– Absence of another well-defined cause of the disease
• Immune-Mediated Inflammatory Diseases:
– Disorders in which chronic inflammation is a prominent component
– Maybe autoimmune, or the immune response may be DIRECTED AGAINST Normally harmless microbes such as Gut commensal bacteria
Autoimmune Disease Examples
ORGAN SPECIFIC:
- Autoimmune Hemolytic Anemia
- Autoimmune Thrombocytopenia
- Autoimmune Atrophic Gastritis of Pernicious Anemia
- Myasthania Gravis
- Graves Disease
- Goodpasture Syndrome
- Diseases Mediated by T Cells
- Type 1 Diabetes Mellitus
- Multiple Sclerosis
- Inflammatory Bowel
SYSTEMIC:
- Systemic Lupus Erythematosus
- Rheumatoid Arthritis
- Systemic Sclerosis
- Sjörgen Syndrome
- Polyarteritis Nodosa
Autoimmune Disease Manifestations
• Vary widely
• Organ-specific disease
– Type 1 Diabetes MELLITUS - β cells of the Pancreatic
Islets
– Multiple Sclerosis – CNS myelin
• Systemic or Generalized Disease
– SLE - diversity of ANTIBODIES directed against DNA, Platelets, Red cells, and Protein-Phospholipid complexes
Immunologic Tolerance
• Process where immune system learns to “tolerate” an antigen
– SELF- TOLERANCE
• Lymphocyte receptors are generated by Random
SOMATIC RECOMBINATION of genes
– Receptors capable of Recognizing SELF Antigens are generated constantly
– These cells MUST BE ELIMINATED or Inactivated as soon as they recognize self antigens
• 2 types:
– CENTRAL tolerance: thymus and bone marrow
– PERIPHERAL tolerance
Central Tolerance- T Cells
• During development, many T cells that express HIGH-AFFINITY TCR’s for self antigens are produced
• “NEGATIVE SELECTION” or “DELETION”– Immature Lymphocytes encounter antigens in the thymus, many die by APOPTOSIS
– Even Peripheral tissue antigens which are processed and presented by thymic antigen-presenting cells
• Some CD4 + T Cells that see self antigens in the thymus DO NOT DIE but DEVELOP into REGULATORY T cells
Central Tolerance- B Cells
• B cells that STRONGLY Recognize Self Antigens in the Bone Marrow:
– Many reactivate the machinery of antigen RECEPTOR Gene REARRANGEMENT and express NEW Antigen Receptors
***** Called “RECEPTOR EDITING”
– If Receptor Editing does not occur, the self-reactive cells Undergo APOPTOSIS
Peripheral Tolerance- ANERGY
• Lymphocytes that recognize self antigens are rendered Functionally UNRESPONSIVE
– Happens when the antigen presented to T cells by APC in periphery GETS NO/ WEAK COSTIMULATORY Molecule Expression
i) Some Tumors and Viruses may use the same pathways of immune regulation to EVADE immune attack
– B cells encounter Self Antigen in peripheral tissues, and in in the ABSENCE of specific Helper T Cells, the B cells become UNABLE TO RESPOND to subsequent antigenic stimulation
Peripheral Tolerance- Suppression by Regulatory T Cells
- REGULATORY T Cells function to PREVENT Immune reactions against Self Antigens
- Mechanisms by which they SUPPRESS Immune Responses are not fully defined
• May play a role in the ACCEPTANCE of the FETUS
– Fetus expresses Paternal Antigens that are foreign to the mother yet have to be tolerated
– Defects in this may lead to recurrent spontaneous ABORTIONS
Peripheral Tolerance- Deletion/ Apoptosis
• T cells that recognize Self Antigens may receive signals that → Death by APOPTOSIS
Immune-Privilege Sites
• Some Antigens are hidden (sequestered) from the immune system
– Do not communicate with the blood and lymph
• E.g. TESTIS, EYES, and BRAIN
• If the antigens of these tissues are released after trauma or infection
– Can → PROLONGED Tissue Inflammation and Injury
Mechanisms of Autoimmunity: General Principles
- Breach of the normal equilibrium of Lymphocyte Activation and Tolerance Mechanisms
- COMBINATION of Genetic Susceptibility and Environmental Triggers
Changes that Contribute to the Development of Autoimmunity
- DEFECTIVE Tolerance or Regulation
- ABNORMAL Display of Self Antigens
- INFLAMMATION or an INITIAL Innate Immune Response
Role of Infection
1) Induction of Costimualtors on APCs:
- Leads to activation of APC —> Self Reactive T Cell
2) Molecular Mimicry:
- Leads to SELF-REACTIVE T Cells that also Recognizes Microbial Peptide
Role of Infection Cont
• Classic Example of molecular MIMICRY is RHEUMATIC HEART DISEASE!!!!!!!!
– Antibodies against STREPTOCOCCAL Proteins CROSS-REACT with MYOCARDIAL PROTEINS and cause MYOCARDITIS
• Some Viruses (e.g., EBV and HIV) cause POLYCLONAL B-cell Activation that can → Production of AUTOANTIBODIES
Infections May Protect Against Some Autoimmune Diseases
- Incidence of Autoimmune Diseases is INCREASING in developed countries
- Infections are better Controlled
- In some animal models (e.g., of type 1 diabetes) infections greatly reduce the incidence of disease
- Possibility because infections PROMOTE Low-Level IL-2 Production, and this is essential for MAINTAINING Regulatory T cells!!!
Micro biome and Autoimmune Diseases
- Normal Gut and Skin Microbiome Influences the DEVELOPMENT of Autoimmunity
- Different Non-Pathogenic microbes affect the relative proportions of Effector and Regulatory T cells, and SHAPE THE HOST RESPONSE towards or away from Aberrant Activation
General Features of AI Disease
- Typically CHRONIC
- Sometimes has RELAPSES and REMISSIONS
- Damage is often PROGRESSIVE
• Can get “EPITOPE SPREADING”
– Immune response against One Self Antigen → Tissue Damage →
release of other Antigens → ACTIVATION of Lymphocytes
• Some AI diseases are caused by Autoantibodies, but MOST are CAUSED BY Abnormal and Excessive TH1 and TH17 responses!!!!!!!!!!!
• Systemic Diseases tend to involve blood vessels and Connective Tissues
– “COLLAGEN VASCULAR” or ”Connective Tissue” diseases
Systemic Lupus Erythematosus (SLE)
- ~1 in 2,500; Women»_space; Men
- African American and Hispanic > Whites
• Autoimmune disease Involving MULTIPLE Organs
– Especially skin, joints, kidney, and serial membranes
- Multiple Autoantibodies, particularly ANTINUCLEAR ANTIBODIES (ANAs)
- Injury is caused mainly by Deposition of Immune Complexes and binding of antibodies to various cells and tissues
- Onset can be Acute or Insidious
- Typically a Chronic, Remitting and Relapsing
- The Clinical Presentation is HIGHLY VARIABLE
Criteria for Classification of SLE
“BRAIN SOAP MD”
B: Blood Hematologic Disorder - Hemolytic Anemia - Leukopenia - Lymphopenia _ Thrombocytopenia
R: Renal Disorder
- Proteinuria
- Cellular Casts
A: Arthritis
I: Immunologic Disorder
- Anti-DNA Abs
- Anti-Sm Abs!!!!!!
N: Neurologic Disorder:
- Seizures
- Psychosis
S: Serositis
- Pericarditis
- Pleuritis
O: Oral Ulcers
A: Antinuclear Ab
- ANA
P: Photosensitivity
- Unusual reaction to Light (UV)
M: Mala Rash
- “Butterfly”
D: Discoid Rash
- Scaling, atrophic Scarring
Antibodies in Systemic Autoimmune Diseases
* All have ANA!!!!!!!***
Antinuclear Antibodies (ANAs)
• Directed AGAINST Nuclear Antigens
• 4 categories:
1) Antibodies to DNA
2) Antibodies to HISTONES
3) Antibodies to Nonhistone Proteins BOUND to RNA
4) Antibodies to NUCLEOLAR ANTIGENS
Detecting ANAs
- INDIRECT Immunofluorescence
- 4 basic PATTERNS of Immunofluorescence:
- Diffuse
- Anti-Centromeric
- Nucleolar
- Speckled
• Pattern can suggest specific diseases, but it’s not absolutely specific
– Antibodies to Double-Stranded DNA and the so- called SMITH (Sm) Antigen are virtually diagnostic of SLE!!!!!!!!!!!!!!!!
Antiphospholipid Antibodies
- ~30-40% of lupus patients
- May cause a FALSE-POSITIVE Test RESULT (VDRL) for SYPHILIS!!!!!!!!!
• Can interfere with Clotting Tests, such as partial thromboplastin time (PTT)!!!!!!
– “Lupus anticoagulant”
– HYPERCOAGULABLE state!!!!
Etiology and Pathogenesis of SLE
• Failure of the mechanisms that maintain self- tolerance
– Cause is unknown
• Thought to involve Genetic and Environmental factors
Genetic Factors in SLE
• Evidence to support a Genetic Predisposition:
A) INCREASED risk of SLE in family members of patients with SLE
B) HIGHER RATE of CONCORDANCE (>20%) in MONOZYGOTIC TWINS compared to dizygotic twins (1-3%)
C) Specific alleles of the HLA-DQ locus have been linked to the production of Anti–Souble-Stranded DNA, anti-Sm, and anti- phospholipid antibodies
D) Some Lupus patients have inherited deficiencies of early complement components → IMPAIRED REMOVAL of Circulating Immune Complexes
• Multiple MHC and non-MHC genes Implicated
• Many Susceptibility loci encode proteins involved in
lymphocyte signaling and interferon responses
– Relative risk for each locus is small
Environmental Factors in SLE
• Exposure to ULTRAVIOLET (UV) LIGHT:
– EXACERBATES the Disease in many individuals
– UV Irradiation may INDUCE APOPTOSIS in cells and may ALTER the DNA in such a way that it becomes Immunogenic
– UV light may also STIMULATE Keratinocytes to produce IL-1 → inflammation!!!!!!!!!
• Gender bias:
– Sex hormones and genes on the X Chromosome
• Drugs:
– Hydralazine, procainamide, and D-penicillamine
• Microbiome?
– “The microbiome–systemic diseases connection”
Morphology in SLE
• BLOOD VESSELS:
– An acute NECROTIZING VASCULITIS involving capillaries, small arteries and arterioles
• JOINTS:
– NON-EROSIVE Synovitis with little deformity!!!!!
(opposite of rheumatoid arthritis)
• KIDNEYS!!!!!!!!!
Kidneys in SLE
• Up to 50% of SLE patients have clinically significant Renal Involvement!!!!!
• All of the GLOMERULAR Lesions are the result of Immune Complex Deposition
– Both in situ formation and deposition of preformed circulating immune complexes
Kidneys Cont in SLE
• 6 patterns of glomerular disease (reasons for different patterns in unknown): 1) Minimal mesangial lupus nephritis (class I): see on EM only (LEAST COMMON)
2) Mesangial proliferative lupus nephritis (class II)
3) Focal lupus nephritis (class III): less than 50%
4) DIFFUSE LUPUS NEPHRITIS (MOST COMMON and Most Severe)!!!!!!!!!!!!!!!!!!!
Skin in SLE
- Characteristic “BUTTERFLY” rash ~ 50% of patients
- Can have a similar rash on extremities and trunk
- EXPOSURE to SUNLIGHT incites or accentuates the erythema
• Immunofluorescence: deposition of immunoglobulin and complement along the DERMAL-EPIDERMAL JUNCTION!!!!!!!!!
– Can be present in Uninvolved skin
– Also seen in Scleroderma or Dermatomyositis
Pericarditis and Other Serial Involvement in SLE
• Inflammation of the serosal lining membranes may be acute, subacute, or chronic
• ACUTE
– Mesothelial surfaces are sometimes covered with
FIBRINOUS EXUDATE
• LATER
– Thickened, opaque, and coated with a SHAGGY FIBROUS TISSUE!!!
– May lead to partial or total obliteration of the serial cavity
• Pleural and Pericardial EFFUSIONS may be Present
Cardiovascular System in SLE
- ANY LAYER of the Heart can be Damaged
- Symptomatic or Asymptomatic pericardial involvement ~50% of the time
- MYOCARDITIS (inflammation of the myocardium) can → Tachycardia and Electrocardiographic Abnormalities
- CORONARY Artery Disease (angina, myocardial infarction)
- VALVULAR Abnormalities, primarily of the MITRAL and AORTIC VALVES→ STENOSIS and/or REGURGITATION
• Valvular (a.k.a. LIBMAN-SACKS) Endocarditis
– Uncommon now b/c of steroids
– NONBACTERIAL Verrucous Endocarditis!!!!!!
Other Organs
• CENTRAL NERVOUS SYSTEM:
– Neuropsychiatric symptoms
i) Non-inflammatory occlusion of small vessels
ii) May be due to endothelial damage by Autoantibodies or Immune Complexes
• SPLEEN:
– SPLENOMEGALY, Capsular Thickening, and Follicular Hyperplasia
• LUNGS:
– Pleuritis and Pleural Effusions ~ 50% of patients
– Chronic Interstitial Fibrosis and secondary Pulmonary Hypertension
Clinical Features of SLE
- Most typically YOUNG WOMEN
- Presentation can be overt or Subtle and Puzzling
- ANAs found in virtually 100% of patients, but not specific for SLE!!!!
• May have signs of RENAL INVOLVEMENT:
– HEMATURIA, Red Cell Casts, Proteinuria, and in some cases the classic NEPHROTIC SYNDROME
• INCREASED numbers of Infections
– Due to underlying Immune dysfunction and treatment with Immunosuppressive Drugs
- Course of the disease is variable and unpredictable
- Disease flares typically treated with corticosteroids or other immunosuppressive drugs
• Causes of DEATH include:
– Renal Failure, Infections, and Coronary Artery Disease
Chronic Discoid Lupus Erythematosus
- Primarily skin manifestations; rarely systemic manifestations
- Skin plaques showing varying degrees of Edema, Erythema, SCALINESS, Follicular Plugging, and Skin ATROPHY surrounded by an Elevated Erythematous border
- Usually FACE and SCALP, but can occur anywhere
Subacute Cutaneous Lupus Erythema
• Presents with predominant skin involvement
• Distinguished from chronic discoid LE by:
– Skin rash tends to be WIDESPREAD, SUPERFICIAL, and NON-SCARRING
• Most patients have MILD SYSTEMIC Symptoms consistent with SLE
Drug-Induced Lupus Erythematosus
- LE-like syndrome may develop in patients receiving a variety of drugs
- E.g. Hydralazine, Procainamide, Isoniazid, and D- Penicillamine
- Also ANTI-TNF therapy!!!!!!! (used to treat Rheumatoid Arthritis and other autoimmune diseases)
- Affects Multiple Organs, but Renal and Central Nervous System involvement is uncommon
- Disease REMITS after WITHDRAWAL of the offending drug
Sjörgen Syndrome
• CHRONIC disease
• Characterized by:
– DRY EYES (keratoconjunctivitis sicca)
– DRY MOUTH (xerostomia)
• From Immunologically mediated DESTRUCTION of the LACRIMAL and SALIVARY Glands
– Lymphocyte infiltration and eventual FIBROSIS
• Can occur on it’s Own or in Association with another autoimmune disease (~60%)
Clinical Features of Sjörgen Syndrome
• Typically seen in women, aged 50-60
• KERATOCONJUNCTIVITIS:
– Blurring of Vision, Burning, and Itching
• XEROSTOMIA:
– Difficulty in SWALLOWING Solid Foods, a Decrease in the ability to taste, cracks and fissures in the mouth, and dryness of the buccal mucosa
• Can Also Have:
– PAROTID GLAND ENLARGMENT
– DRYNESS of the Nasal Mucosa and Epistaxis
– Recurrent Bronchitis and Pneumonitis
– Synovitis
– Diffuse Pulmonary Fibrosis
– PERIPHERAL Neuropathy
– RENAL: Renal Tubular Acidosis, Uricosuria, and Phosphaturia
