15. autoimmune diseases Flashcards
immunologic tolerance
Inability of immune system to set immune response to a specific self-antigen is immunologic tolerance
2 type of tolerance
central and peripheral tolerance
Mechanisms of development central tolerance
T cell central tolerance, additional sources of antigen are made available in the thymus by the action of the transcription factor AIRE (autoimmune regulator).
Positive selection
Negative selection
Mechanisms of development of peripheral tolerance
colonal anergy
colonal deletion
peripheral suppresion by t cells
ag sequestration
Clonal anergy;
Prolonged or irreversible inactivation of lymphocyte
Costimulator deficient antigen-presenting cells (APCs)
B7 - CD28
Clonal deletion by activation-induced cell death
Fas by Fas L induces apoptosis
Peripheral suppression by T cells
Regulatory T cells produce anti inflammatory cytokine
IL4, IL10 and TGFβ
Antigen sequestration
Tissues not communicate with the blood and lymph, eg, testis, eye and brain
organ specific autoimmune diseases
autoimmune hemolytic anemia
autoimmune thrombocytopeni
autoimmune pernicous anemia
myasthenia gravis
graves disease
goodpasture sydrome
type 1 DM
multiple scelerosis
crohns diesease
primary biliary cirrhosis
AI hepatatis
systemic
SLE
rhematoid arthriitis
sclerodemra
sjogrens sydrome
polyarteritis nodosa
inflammatory myopathies
Mechanisms of Development of Autoimmunity
Breakdown of T cell anergy ; express costimulatory molecules
Failure of activation-induced cell death; congenital or acquired defects in the Fas–Fas ligand system
Molecular mimicry; cross-reaction between antibodies against infective agents with self-antigens
Polyclonal lymphocyte activation
Failure of T cell-mediated suppression
Release of sequestered antigens (anatomic sequestration)
Exposure of cryptic self-antigens and
epitope spreading (molecular sequestration)
The systemic diseases tend to involve blood vessels and connective tissues . they are often called
collagen vascular diseases or connective tissue diseases
Systemic lupus erythematosus(SLE)
Classical prototype of a multisystem autoimmune disease
Chronic, remitting and relapsing illness
M:F = 1:9
Peak incidence is age 20-45 years
Type II and III hypersensitivity reactions.
anti what antibodies
Antinuclear antibody (ANA) (>95%);
anti-dsDNA (40 - 60%);
anti-Sm (20-30%);
……………..and ……………..are virtually diagnostic of SLE.
Anti-Sm and ds DNA are virtually diagnostic of SLE.
pathogenesis of SLE
In this hypothetical model, susceptibility genes interfere with the maintenance of self-tolerance, and external triggers lead to persistence of
nuclear antigens. The result is an antibody response against self nuclear antigens, which is amplified by the action of nucleic acids on dendritic cells (DCs) and B cells, and the production of type 1 interferons. IFN, Interferon; TLRs, Toll-like receptors.
ag ab complex deposit in tissue
inflamation
…………….. impairs removal of circulating immune complexes
Inherited deficiency of early complement components
……….. are linked to the production of anti-ds DNA, anti-Sm and AP antibodies
HLA-DQ
drugs induce sle
Drugs (hydralazine and procainamide)
clinical manifestations specific 4
butterfly rash
discoid rash
alopecia
raynauld syndrome
lupus erythematous cell
neutrophils
engulfed ag ab comples
nucleus pushed to periphery
kidney sle
lupus nephritis
classification of lupus nephritis 6
class 1 minimal - normal
class 2 mesangial prolerative - microscopic hematuria
class 3 focal lupus nephritis- hematuria proteinuria
class 4 diffuse- like 3 but with decresed c3 and highdsDNA
class 5 membranous nephropathy-nephrotic syndrome
class 6 advanced sclerosing lupus - renal fail
class 3 and 4 present with
wire loop lesions thickening of capill
hematoxylin bodies - LE cells
hyaline thrombi - aggregation of complex
spleen sle
Capsular thickening,
follicular hyperplasia,
increased plasma cells and
thickening of penicilliary arteries (onion skinning)
skin sle
liquefactive degeneration of the basal layer of the epidermis and
edema at the DEJ -derm epiderm junct
heart sle and whts the special name
vegetation on mitarl valve
libman sacks endocarditis
Drug-Induced Lupus Erythematosus
Hydralazine,
procainamide (80% positive for ANAs, 1/3 become symptomatic),
isoniazid, and
D-penicillamine
Anti-TNF therapy
Renal and CNS involvement is uncommon
Drug-Induced Lupus Erythematosus
serologic finding
Anti-histones Ab»_space;> Anti dsDNA Ab
Antiphospholipid antibody syndrome
1° or 2° autoimmune disorder (30% of SLE)
…………….. can cause false positive VDRL (syphilis test) …. type of antiphospholipid
Anticardiolipin antibodies
……………. can cause prolonged PTT that is not corrected by mixing study … type of antiphospholipid
Lupus anticoagulant
complications of antiphospholipid ab syndrome
Arterial and venous thrombosis
(DVT, hepatic vein thrombosis,
placental thrombosis (recurrent pregnancy loss), and stroke)
triggers for APA syndrome
trauma
infection
non immune procoagulant
what antibody exerts protective effect
anti lamin b1 ab
Sjögren’s syndrome
triad
dry mouth
dry eye
inflammatory arthritis
1ᵒ = sicca syndrome and 2ᵒ associated with other autoimmune disease (RA)
what antibodies plus types
~80% anti-ribonucleoprotein antibodies
SS-A (Ro) and SS-B (La)
An increased incidence of ………. seen in sjogren
Marginal zone lymphoma (low grade B-cell lymphoma)
non hodgkins type
manifestations or sicca syndrom
dry eye
dry vagina
dry skin
dry mouth
palpable pupura
raynauld sydrome
enlarged salivary gland (bilateral parotid swelling)
Systemic sclerosis character
Characterized by: (1) chronic inflammation (autoimmunity) (2) damage to small blood vessels, and (3) progressive interstitial and perivascular fibrosis in the skin and multiple organs.
pathogenesis
external stimuli
endothelial damage
vasculopathy
ischemia repair fibrosis
or
genetic susceptability plus external stimuli
t and b activation
profibrotic cytokines
fibrosis
profibrotic cytokines
TGF B
IL14
PDGF
2 types of scleroderma
diffuse and limited
Diffuse scleroderma —
widespread skin involvement,
rapid progression,
early visceral involvement.
Anti-Scl-70 antibody (anti-DNA topoisomerase-I antibody) and anti-RNA polymerase III.
Limited scleroderma and crest syndrome
limited skin involvement confined to fingers and face.
anti-Centromere antibody
CREST syndrome:
Calcinosis cutis C ,
Raynaud phenomenon,
Esophageal dysmotility,
Sclerodactyly, and
Telangiectasia.
dermatomyositis
inflammatory cells around border of muscle fibers
both skin and muscle
perimysial inflammation
cd4 t cells
manifestations
heliotrope - eyelid rash purple like flower
malar or butterfly rash
shawl sigh
guttrons papule
calcinosis cutis
ground glass opacity of lungs
polymyocitis
inflammatory cells invade muscle fibers
endomysial inflammaion
cd8 t cells
manifestations
trouble raising hand and leg
Mixed connective tissue disease
An overlap condition with features of SLE, systemic sclerosis, and polymyositis
Typically presents with synovitis of the fingers, Raynaud phenomenon, myositis, and renal involvement
Anti- U1 ribonucleoprotein are nearly always positive
IgG4-Related Disease(IgG4-RD)
Constellation of disorders characterized by tissue infiltrates dominated by IgG4 producing plasma cells and lymphocytes (particularly T cells), fibrosis and obliterative phlebitis
Usually increased serum IgG4
Middle age and older men
Ideopathic; It is unclear if the disease is truly autoimmune in nature, and no target autoantigens have been identified.
Rituximab provided clinical benefit
IgG4-Related Disease(IgG4-RD)
manifestation mnemonic
pairs
pancreatitis
interstitial nephritis
riedel thyroditis
retroperitoneal fibrosis
scelerosing sialadentis = salivary
what syndrome seen in IgG4 related disease
mikulicz syndrome
lacri sali enlargement
Immunodeficiency classifications
defect on first line second or third line defense
first line deficinecy
burn
viral infection
primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD)
.PCD is inherited in an autosomal recessive manner with the exception of FOXJ1-PCD (which is autosomal dominant) and PIH1D3-PCD and OFD1-PCD (which are X-linked).
Kartagener syndrome (50% of PCD) is a subgroup of the immotile cilia syndrome
triad
dextro cardia
bronchiectasis
sinusitis
Abnormalities of cilia include
absence of both inner and outer dynein arms, absence of spoke heads, and absence of one or both central microtubules.
defect in second line defense
leukocyte adhesion deficiency
Chédiak-Higashi syndrome
Deficiencies of oxygen-dependent killing
complement defect
leukocyte adhesion deficiency 1 special
AR
deficiency of B2 integrin or CD18
recurrent bacterial infection and umlical doesnt heal
Chédiak-Higashi syndrome 1 special
AR
Characterized by neutropenia defect in chemotaxis and degranulation (LYST mutation)
partial albinism
What is seen in all chediak higashi syndrome WBCs
abnormal granules
Deficiencies of oxygen-dependent killing
2 types
Chronic granulomatous disease of childhood:
Myeloperoxidase deficiency
Chronic granulomatous disease of childhood: ntt result
XR/AR
Absence/deficiency of NADPH oxidase
Recurrent bacterial infections with catalase-positive organisms (S. aureus)
NTT will be -Ve nitro tetrazolium test
Myeloperoxidase deficiency ntt result
AR
Infections with Candida
NTT will be +Ve
complement defects plus types
C5, C6, C7, C8, Factor B and properdin deficiencies increased Neisseria infections
C1q, C1r, C1s, C2, C3 and C4 deficiencies increases in immune complex diseases and recurrent bacterial infections
2 types
Hereditary angioedema
paroxysmal nocturnal hemoglobinuria
Hereditary angioedema
defect in C1 esterase inhibitor
c1 esterase produce bradykinin
which increase permeability
so edema
PNH
defect in PIGA
leads to complements not being inhibited so hemolysis
black urine
third line defense defect list 7
X linked agammaglobulinaemia - XLA
Common variable immunodeficiency (CVID)
selective IgA deficiency
DiGeorges syndrome
SCID
Hyper IgM syndrome
wiskotts aldrich syndrome
X-linked agammaglobulinaemia (XLA )
= Bruton disease
Failure of B cell maturation and absence of gammaglobulin in the blood
Mutations on Bruton’s Tyrosine Kinase (BTK) gene
Manifests by about 6 months of age
Recurrent bacterial or viral infections and giardia lamblia infections
Common variable immunodeficiency (CVID)
Heterogeneous group of disorders
Defect in B-cell differentiation and antibody production due to unknown cause
Plasma cells are absent, perhaps due to a block in antigen-stimulated B cell differentiation
May present in childhood but usually diagnosed after puberty (onset in second decade)
↑risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections
selective IgA deficiency
most common primary
low IgA but others all normal
high penetration of allergens through the mucosa due to defective serum and mucosal IgA
DiGeorge syndrome
Absence of the parathyroid glands and thymus
hypocalcemia and tetany
T-cell deficiency viral and fungal organisms
Deletion of chromosome 22q11.2
DDiGeorge syndrome mnemonic
catch 22
cardiac problems
abnormal facies
thymic aplasia
cleft palate
hypocalcemia
Severe combined immunodeficiency (SCID)
Deficiency of cell-mediated and humoral immunity
Often caused by a progenitor-cell defect
Recurrent viral, bacterial, fungal, and protozoal infections
Most infants die of infection within a year
types of SCID
Types
IL-2R gamma chain (most common,XR);
Adenosine deaminase deficiency (AR);- purines defect toxic
RAG mutation - VDJ recombination defect
Hyper-IgM syndrome
Most commonly due to defective
CD40L(X-linked recessive) on Th cells
Class switching defect; Normal or ↑IgM and↓IgG, IgA, IgE
Failure to make germinal centers
Wiskott–Aldrich syndrome
Due to mutations in WASP gene so defect in APC
Age related depletion of T lymphocytes
Inability to synthesize antibodies to polysaccharide antigens (encapsulated pyogenic organisms)
↑risk of autoimmune disease and NHL
Ab number
IgM decreased
IgG same
IgE and IgA high
wiskott aldrich triad
water
thrombocytopenia
eczema
recurrent infection
Hv
Fg
