Transcript Autoimmune Diseases

Autoimmune Diseases
Systemic autoimmunity (#03)
Organ-specific autoimmunity (#04)
Allergic diseases (#05)
- intro • Key feature of immune responses:
• -target the pathogen
• -orchestrate the local/regional*
inflammatory reaction, eliminating the
antigen without extensively damaging the
host’s tissue
• -manage the repair
• Extensive deleterious effects =>
hypersensitivity (allergy)
• SPECIFIC IMMUNTY:
• sensitization phase (abnormal immune
response in terms of type, taget, clearance)
• (memory induction)
• elicitation phase
The four types of hypersensitivity reactions, PGH Gell and RRA Coombs (Kuby 5th Edition
2002, Fig. 16-1)
• IgE-mediated TYPE I
• (cytotoxic/cytolytic) antibody-mediated
TYPE II
• immune complex-mediated TYPE III
• delayed-type hypersensitivity TYPE IV
Antibody-mediated Hypersensitivity, Type II
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Detrimental effects:
- lysis via Complement System activation
-ADCC
-phagocytosis (Fc/C3b and others)
Classical models: transfusion reactions,
hemolytic disease of the newborn, druginduced hemolytic anemia
Antibody-mediated Hypersensitivity, Type II
(Kuby 5th Edition
2002, Fig. 16-13)
Antibody-mediated Hypersensitivity, Type II
(Kuby 5th Edition 2002, Fig. 16-14)
Immune complex-mediated Hypersensitivity, Type III
• Detrimental effects:
• - deposition of immune complexes formed either in the
bloodstream, or locally
• -complement activation, neutrophils involvement
(regurgitation of organelle components)
• Classical models: local forms: alveolitis, pneumonitis due
to bacterial spores, fungi, dried fecal proteins of parasites Arthus reaction, farmer’s lung; systemic forms: serum
sickness due to horse antitetanus or antidiphteria serum
• SLE, RA, Goodpasture syndrome, Allergies to penicillin
and sulfonamides, poststreptococcal glomerulonephritis,
meningitis, hepatitis, mononucleosis, malaria,
trypanosomiasis
Immune complex-mediated Hypersensitivity, Type III
(Kuby 5th Edition 2002, Fig. 1615, 16)
Delayed-Type Hypersensitivity, Type IV
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Detrimental effects:
- local recruitment of monocytes/macrophages
-Langerhans cell, Th (in some instances Tc): TDTH, Th1
granuloma formation; cytokines (MCAF, monocyte
chemotactic and activating factor, MIF, migrationinhibition factor; IFNgamma, TNFbeta); NO
• Classical models: contact dermatitis; tuberculous reaction
Delayed-Type Hypersensitivity, Type IV
(Kuby 5th
Edition 2002,
Fig. 16-15, 20)
Autoimmune Diseases
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(AID): immune responses mounted against self components that result in
pathology.
Prevalence: higher with age, in developed countries (~3-5%); major cause of
death for women under age 65.
1890s: Paul Ehrich ‘horror autotoxicus’ concept
1900s: reports of autoreactivity (anti-self agglutinins, J.Donath &
K.Landsteiner; rabbit anti-self ocular proteins as immunogens; cross-reaction
of human anti-Treponema pallidum with self antigens - later cardioipin;
rheumatoid factor, in 1930s, as being able to agglutinate indicator - coated
with IgG - sheep RBCs)
1950s: WJ Harrington: platelet depletion effect of serum from patients with
idiopathic thrombocytopenic purpura (=> autoantibodies); Peter Miescher and
Henry Kunkel: antibodies against self DNA, RNA and various nuclear
proteins; Noel Rose: immunization of the rabbit with self thyroid induces
thyroiditis.
1960s: New Zealand, Marianne and Feliz Bieloschowsky: NZB inbred mice
that died prematurely of an AID similar to autoimmune hemolytic anemia;
further breeding: kidney, thymus
Autoimmune Diseases
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1960/70s: clarification of T and B lymphocytes, MHC; fluorescence
microscopy for detection of autoantibodies on cell surfaces and serum; GF
Bottazo, WJ Irvine independently demonstration of anti-pancreatic beta-islet
cell antibodies in IDDM
1990s: DC subsets, Th subsets; PCD (apoptosis and other forms) mechanisms.
Currently more than 80 distinct disorders (previously considered as
‘idiopathic’):
Saunders, Mak,
2006, F 29.1
Autoimmune Diseases
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Failure of tolerance mechanisms:
-CENTRAL TOLERANCE (the only clear example is APECED, autoimmune
polyendochrinopathy candidiasis ectodermal dystrophy, in human, with defects
in AIRE function/nuclear localization, and NOD - T1DM non-obese diabetic
mice)
-PERIPHERAL TOLERANCE (often associated with certain allelic variation
in genes encoding immune defense factors, and revealed by environmental
triggers, cytokine context).
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In healthy individuals: even when autoreactive clones emerge, intact
mechanisms of PT suppress and limit the tissue damage.
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Traditionally, based on clinical observation: organ-specific / systemic
autoimmunity (paradoxes such as primary biliary cirrhosis, with antimitochondrial antibodies, or Sjogren with anti-nuclear antibodies; SLE, with
targets at distant sites from the originating antibody-antigen complexes).
Autoimmune Diseases
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Saunders, Mak,
2006
Systemic Lupus Erythematosus
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=> idiopathic
large spectrum of clinical manifestations / variability of disease progression with
relapses and remissions
targets every organ system; often initially affects the skin, joints, kidney, lung, heart,
gastrointestinal tract
more frequently young women (9:1 in adults), Asians; African-Americans; strong
concordance rates in monozygotic twins (~50% involving MHCs - DR2, DR3,
DRB1*1501, DRB1*1503, DR3 & C4A null, complement - deficiencies in C1q, C4,
C2, C1s and C1r; FcRgII-R131 and III genes, apoptosis; IL-1Ra); with alopecia, fatigue,
musculoskeletal symptoms, vascular abnormalities, photosensitivity, characteristic rash
(red, erythematous, affecting the malar region of the face - wolfish appearance).
Multiple elements of the immune system may be disrupted (including complement, with
opportunistic infections).
Incidence ~40 / 100 000.
Antinuclear antibodies (ANA), against dsDNA (fluctuanting with flare-ups), and against
small ribonucleoproteins (snRNPs, like Smith -Sm- antigen) exposed by cell necrosis
(rather constant in titers).Other targets: histone proteins, RNA-binding proteins, DNA
polymerase components, cytoplasmatic and membrane phospholipids, IgG, coagulation
factors, complement components
Systemic Lupus Erythematosus
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These autoantibodies form circulating immune complexes
accumulating in target organs; sometimes may be also
kidney antigens as targets.
The pattern of autoantibody tends to be conserved for given
patients.
B lymphocytes are abnormal: increased numbers in
circulation, activated cells of all stages, elevated (beyond
basal) levels of cytoplasmatic Calcium; higher responsivity
to cytokines.
Higher circulating levels of IL-10 (activatory cytokine for B
lymphocyte proliferation and differentiation), sometimes
corelating with ANA titers
monocytes/macrophages inefficient producers of IL-12
defects in AICD of Th
High affinity antibody throughout of the evolution (although
both Td and Ti autoantibodies are pathogenic)
unknown positive reactivity for Th cells
Systemic Lupus Erythematosus
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Mechanisms
genetics
environmental factors NO CAUSATIVE FACTORS, but triggers
UVB=> flares of both cutaneous and internal organ lupus (some antigens,
like Ro, La, RNP, but not chromatin antigens and other nuclear components
are translocated to keratinocyte cell surface, favorising the immune
response); decrease DNA methylation and induces gene expression; increase
expression of integrins like LFA-1
weaker correlation with viral infections (EBV, via CD21, as stimulator of B
lymphocytes; mimicry of EBNA II / Sm antigens with partial sequence
homology), high-fat and high-caloric diets, cosmetics, trichloretane, but
greater with stress, depression, fatigue
contribution of estrogens / low levels of DHEA
drug - induced (procainamide - slow acetylator phenotype due to decreased
acethyltransferase activity in p450 cytochrome system, with predominance of
anti-histone antibodies)
Systemic Lupus Erythematosus
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• Take home topics:
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animal (murine) models of SLE
abTCR lymphocytes in SLE
Intrinsic defects of B lymphocytes in SLE
Complement system in SLE