Immunopathology Flashcards
Acquire immunity Hypersensitivity Auto-immunity Immuno-deficiency
What involve in acquired immunity
. Specific antigen
. Lymphocytes T (virus) and B (bacteria)
. Memory
Another name for acquired immunity
Adaptive immunity
What’s the name for adaptive immune response to extracellular microbe (i.e. bacteria)? What regulated this process?
Humoral immunity
B lymphocytes
What’s the name for adaptive immune response to intracellular microbe (i.e. virus)? what regulated this process?
Cell-mediated immunity
T lymphocytes
What B cells produce? How do they cause destruction of microbes?
Antibody: IgM first then IgG, IgA, IgE in bone marrow
Phagocytosis by PMN and Mø
What T cell produce? How do they cause destruction of microbes?
CD4 T helper cell: cytokines (Th1, Th2, Th17, Treg)
Cytokines activate and proliferate CD8 Tcells
CD8 T cytotoxic cell: apoptosis
What are key features of antigens?
. bound to aB - immunogen
. high molecular weight (MW>10,000) proteins
. sometimes carbohydrate
What is epitopes?
. Smaller fragments of antigens
. recognized by antigen combining site of aB or T cell R
. Comprised 8 AA (linear-T cell) or up to 20 AA (globular-B cell)
Dendritic Cells prime T cells involve in
- Endocytosis
- Toll-like Receptor (TLR) Ligation
- Increase expression of MHC-1 co-stimulatory molecules
- antigen presentation
Another name for MHC (major histocompatibility complex)
Human leukocyte antigen (HLA)
Where does MHC-II/HLA present to?
CD4 T helper cells
Where does MHC-I/HLA present to?
CD8 T cytotoxic cells
What are the 3 main signals to activate T cell?
- MHC and peptide on DC present specific antigen : T cell R on T cell
- Co-stim signal CD80/CD86 of DC : CD28 of T cell
- CD40 on DC : CD40L on T cell
Timeline of generating T cell response
4-5d : activate cytokines from Th1, Th2 and Th17
7-10d: activated T cytotoxic cell (with help of Th1)
1-2d : once memorized!
What are the 2 main cytokines that stimulate Cytotoxic T cells?
IFN-a and TNF-a by Th1
Primary role of Cytotoxic T cell?
Apoptosis
e.g. cancer tumour is a target of T cell killing
What are main signals to activate B cell?
MHC-II / peptide / TCR
CD40 on DC : CD40L on activated Th cells
How long does it take to activate B cell, to switch from IgM to IgG for the first time?
10 days
How many heavy and light chains in each aB?
2 heavy
2 light
Where in the aB determine the Ig isotypes?
Constant region of Heavy chain
- What aB has the lowest affinity to antigen?
2. What aB has the highest quantity in serum?
- IgM
2. IgG
What included in adaptive immunity? (important)
Humoral immunity (aB)
Cell-mediated immunity (T cell)
Tolerisation (autoimmunity)
Hypersensitivity (second-line exposure of allergen)
What is the primary role of B cell?
produce immunoglobulin (aB)
Can innate immunity involve T cell?
NO
only mast cell, Mø, NK cells and N˜
What is the main feature of hypersensitivity?
Only occurs on the SECOND (subsequent) exposures to antigen
Hypersensitivity rx are induced by allergens. List some examples of Allergen
. small soluble proteins or glycoproteins . proteases . dust mite faeces . food (milk, nut,...) . insect saliva . drugs (penicillins, aspirin)
Main features of Type 1 hypersensitivity
. IMMEDIATE type
. IgE bound to mast cells (cross linking lead to degranulation)
. IL-4,5 from Th2 mediate IgE production
Predisposing factors to ATOPIC allergy (type 1 hypersensitivity)
. High affinity for IgE on mast cells and basophils
. Higher IgE levels (if >1µg)
. Genetic predisposition (Favor Th2- IL-4)
. Environmental pollutants can increase IgE (inhibit Th2 func and inhibit tolerance induction)
note: neonates may develop allergies if exposed to pollutants simultaneously (can train them)
In Type 1 Hyp, what lead to immediate response and what are those responses?
Degranulation of mast cells causes release of Histamine, proteases and chemotactic factor
- vasodilation
- vascular leakage (to tissues)
- Smooth m/s spasm
In Type 1 Hyp, skin rx to allergen peaks at __ mins, called __&__
In Type 1 Hyp, systemic manifestation is called __ shock
__ primes __ to migrate in response to chemotactic factors, called __ asthmatics
30 mins
wheal and flare (blister and red)
anaphylaxis
IL-5
Eosinophils
extrinsic
List some examples of local anaphylactic Type 1 Hyp
Allergic rhinitis - Hay fever
Asthma (smooth m/s)
Atopic eczema or urticaria
Food allergy (GIT)
Type 1 Hyp PATHOLOGICAL processes
. Smooth m/s contraction
. Vasodilation - fluid exudates
. Mucus secretion exceeded
. Eosinophil infiltration
Main features of Type 2 Hyp
. Cell-bound antigen coated with IgG
. Cells are opsonized by C3b
. Followed by phagocytosis destruction
. Complement cascade forms membrane attack complex (MAC)
Type 2 Hyp: Clinical examples
. Incompatible blood transfusions . Hyperacute graft rejection . Myasthenia gravis . Graves disease . Acute rheumatic Fever . Drug hyp
Main features of Type 3 Hyp
. immune COMPLEX-MEDIATED
. IgG bound to SOLUBLE antigen
. Arthus rx skin test peaks at 3-8hrs with infiltration of polymorphs
. Complement activation generates anaphyatoxins and attract polymorphs
. ‘Frustrated’ phagocytosis due to C’s mediated inflam
What can Ag:Ab complex (immune complex-mediated hyp) activate?
- Platelet aggregation
- Complement (anaphylatoxin and polymorphs)
- Mø
Something special about Type 3 Hyp
Have 3 phases
- formation of immune complex
- deposition of immune complex
- immune complex mediated inflammation
In local vs. systemic rx of Type 3 Hyp
. Excess __ lead to precipitated immune complex. E.g. __
. Excess __ gives soluble immune complexes. E.g. __
aB
Pigeon Fanciers Disease
antigen
Serum sickness or deposition of immune complexes in kidney glomerulus
Main features of Type 4 Hyp
. DELAYED types
. T-cell mediated response (cytokines IFN-g, GM-CSF)
. Skin test - infiltration of mononuclear cells peaking at 24-48hrs (Th recruit Mø)
. Diagnostic for T cell immunodeficiency
Type 4 Hyp examples of reaction
AIDS
Contact dermatitis (e.g nickel)
TB
chronic granuloma
What’s special about Type 4 Hyp in the skin?
Staining of CD4 T cell (granuloma)
Immediate vs. Delayed Hyp type
. ITH develop in _ mins while DTH develop in _ hrs
. Central appearance is _ for ITH & red induration for DTH
. Peripheral appearance is _ for both ITH & DTH
. __ cells (Ig_) involved in ITH & __ cells involved in DTH
30mins
24-48 hrs
blister
red
Mast cells (IgE) Th cell
What is another term for autoimmunity?
Tolerisation
What is tolerisation
. prevents auto-reactivity in the thymus, but:
. auto-reactive cells destroyed by apoptosis
. low affinity auto-reactive T cells may ‘escape’ deletion in the thymus
note: auto-aB and auto-reactive t cells can be found WITHOUT accompanying disease
What does NON-self reactive clones of T cell do?
enter periphery for normal immune func
What are Regulatory T cells and what do they control?
Tregs: CD4, CD25, FoxP3+ cells
Control T cell proliferation by production of IL-10 + TGF-b
note: regulatory effect depends on cell-cell contact
Features of autoimmune disease (7)
. increase mononuclear cells infiltration [lymphocytes, Mø, and p/m cells]
. Loss of tolerance to self
. genetic predispositions HLA
. Classified by 4 Hyp types
. Female bias
. Patient often have multiple autoimmune disease (systemic, local)
. Environmental influences
4 SYSTEMIC autoimmune diseases
SLE (Systemic Lupus Erythematosus)
Sjögren’s syndrome
Scleroderma
Rheumatoid arthritis
How does the immune system recognise self
. HLA present unique antigens (Genetic susceptibility)
. Molecular mimicry
. Following infection and tissue damage
SYSTEMIC autoimmune disease (1)
SLE
. Caused by: lots of auto-aB forming immune complex
. Major auto-aB: at nuclear antigens (ANAs)
. Manifestations: nephritis, skin lesions, arthritis
. Disease remitting and relapsing
. common, esp. 20-30s yrs
In SLE, what are inherited susceptibility and environmental triggers
. inherited: MHC-II and complement
. environment: UV radiation
Diagnosis of SLE
. Photosensitivity
. Rashes
. Arthritis (joint pain?)
. Disorder (renal, neurological,…)
note: SLE can affect skin, joints, kidney, etc.
SLE associate with what types of Hyp?
Type 2 and 3
SYSTEMIC autoimmune disease (2)
Systemic sclerosis
. Also called scleroderma
. accumulation of fibrous tissue in skin others (=increase collagen production)
. CD4 T cell involved
. female bias (older women)
Possible mechanism for sclerosis
Cytokines (growth factors) and Ischemia to increase fibrosis/collagen)
SYSTEMIC autoimmune disease (3) Rheumatoid arthritis (RA)
. Increased TNF cytokines activate B cell, Mø and endothelial cell
. Involve rheumatoid factor and fibroblast
. Pannus formation
treat: have aB bound therapy to clean up TNF cytokines
SYSTEMIC autoimmune disease (4)
Sjögren syndrome
. Destruction of exocrine glands (lacrimal and salivary glands)
. Symptoms: dry eyes and mouth
. infiltration of CD4-T and B cells
. Female bias (older women)
. Have rheumatoid factor and 50% have ANAs
What is rheumatoid factor and ANAs?
Rheumatoid factor = aB bind and form immune complex with IgG. Involved in RA and Sjögren syndrome
ANAs = auto-aB directed at nuclear antigens
4 LOCAL autoimmune diseases
Multiple sclerosis (neuro) Hashimoto's Thyroiditis (endocrin) Type 1 diabetes (endocrin) Crohn Disease (GIT)
LOCAL autoimmune disease (1)
Multiple sclerosis
. Demyelinating disorder . occur at any age . female bias . Caused by: CD4 T cells (specific for antigens from myelin sheath) . Th1 cells activate Mø . Relapsing - remitting disease
LOCAL autoimmune disease (2)
Hashimoto’s Thyroiditis
. HYPOthyroidism (destruction of thyroid)
. thyroid epithelial cells are destroyed by:
- CD8 (direct destruction)
- CD4 (toxic cytokines)
- auto-aB and ADCC
What appear in histological feature of Hashimoto’s thyroiditis
. Thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centre
LOCAL autoimmune disease (3)
Type 1 diabetes
. B-islet cells of pancreas attacked by CD8 T cells (also CD4 T)
. pancreas no longer making insulin
. may associate with viral infection
. Have class2 alleles (HLA-DR3,4) in most of Caucasians
LOCAL autoimmune disease (4)
Crohn’s disease
. Lesions along GIT
. HLA-DR1 association
. NOD2 involvement (inflammasome)
. CD4 T cell activation and granulama formation (site of necrosis)
Gross pathology of Crohn’s Disease
- mucosal ulcers and thickened intestinal wall
- perforation and ass. serositis
- creeping fats
Main types of Immunodeficiency
Primary and Secondary Immune Deficiencies
What are deficiencies in the INNATE response
Defective in:
- production of polymorphs
- response to chemotactic stimuli
- leucocyte adhesion (LFA-1 defect)
- lysosomes (pyogenic infections)
- no production of reactive O2 intermediates
What infections occur in deficiencies of complement, in innate response?
Pyogenic infections (immune complex disease) Neisserial infections
Is deficiency in innate response the same with acquired immune response?
NO
What are indications of T lymphocyte immunodeficiency?
. reduce CD3+ T lymphocytes (genetic marker)
. variations of circulating CD4+ and CD8+ lymphocytes (AIDS)
. low response to polyclonal activators (Concanavalin A)
. decreased type Hyp
. changes of T cells area in the lymph node
What are indications of B lymphocyte immunodeficiency?
. reduced aB (Ig+ve)
. reduce opsonisation
. poor response to polyclonal activators (LPS in vitro)
. poor aB response to vaccination with inactivated vaccines
. increased susceptibility to pyrogenic infections
Examples of Primary immunodeficiency Disorder
T+B - Severe Combined Immunodeficiency Disorder (SCID) T - DiGeorge Syndrome T+B - Bare Lymphocyte Syndrome B - X-linked agamma-globulinemia B - Hyper IgM syndrome
Which primary immunodeficiency is classified as stem cell disorder
SCID
What are the 2 factors causing SCID?
ADA deficiency and cytokine signaling mutation
- ADA: enzyme in purine metab
- cytokine mutation: result in no growth factors for cell survival
What is sad for SCID patient?
highly susceptible to infection
‘Bubble’ boy
Which primary immunodeficiency disorder has FAILURE of B cell?
X-linked Agammaglobulinemia
aka Brutons disease
Which primary immunodeficiency disorder has ELEVATED levels of B cell? specific Ig type involved?
Hyper IgM Syndrome
- increase IgM and reduce IgG+A
What is the cause of Hyper IgM deficiency?
deficiency in:
- CD40L, CD40
- activation-induced cytidine deaminase (AID)
- Uracil DNA glycolase (UNG)
Which primary immunodeficiency disorders with little/no thymus gland?
DiGeorge Syndrome
- so no development of T cell for cell-mediated response
Which primary immunodeficiency disorder has lack of MHC-II?
Bare Lymphocyte Syndrome
- so no activation of CD4
- also reduced IgG, IgA
What is one common thing in patient with primary immunodeficiency disorders?
very susceptible to infections
Secondary immunodeficiency can be seen in patients with:
. autoimmune disease . neoplasms . measles, chicken pox, mumps, severe trauma leprosy, Hodgkins disease . malnutritions . HIV-AIDS . Cancer or infection
In Secondary immunodeficiency, patient with INFECTION (i.e. measles) have predominance of what?
. strong Th1 response but also require Th2 response
In Secondary immunodeficiency, patient with NEOPLASMS have predominance of what?
. one type of WBC (i.e. B cells in myeloma)
. also absence of WBC due to chemotherapy
Does AIDS classified as primary or secondary immunodeficiency?
Secondary
What is AIDS
Acquired immune deficiency syndrome
. gp120 glycoprotein of RNA retrovirus infecting CD4 T cells
. Co-factor required
. associated with Type 4 Hyp
What are co-factor required for AIDS
members of chemokine receptor family
- Mø tropic HIV : CCR5
- lymphotropic HIV: CXCR4
In AIDS patient, where has higher CD4 for HIV-RNA retrovirus to bind to?
Th cells (compared to Mø and DC)
AIDS patient is susceptible to what?
Mycobacterium tuberculosis
