W05 - IMM.: Hypersens; AuImm.; 1º Immunodeficiency

Question 1

Contrast the mechanisms of Types I, II, III and IV hypersensitivity.

Answer 1

I - immediate,

II - cell-bound ag.,

III - immune complex,

IV - delayed,

V

Question 2

Define the roles of allergen, IgE, mast cells, inflammatory cells, mediators and cytokines in Type I hypersensitivity.

Answer 2

IgE = trigger immediate hypersensitivity, which manifests as allergy symptoms such as asthma or rhinitis
* instant onset if IgE preformed
* adaptive immune response mediator

Mast cells and eosinophils act as innate immune system mediators => degranulate

= allergy, hypersens.

Question 3

Explain the pathophysiology of early and late phase allergic reactions.

Answer 3

B cells produce IgE when co-stimulated with IL-4 (secreted by TH2 cells)

=> IgE

=> MC degran across tissues, eosinophils localise
- prostaglandins and leukotrienes (mucus & smc conrtraction) via cyclooxygenase and lipoxygenase
+ histamine in skin
=> vasodilation = permeability

Question 4

Define atopy.

Answer 4

Immediate hypersensitivity reaction to environmental antigens mediated by IgE.

Question 5

Illustrate the clinical effects of Type I Hypersensitivity.

Answer 5

Rhinitis, Asthma, Anaphylaxis, Dermatitis

• angioedema
• eczema
• acute urticaria

Question 6

Define the roles of antibody, complement, Fc receptor bearing cells and ADCC in Type II hypersensitivity.

Answer 6

Ab-mediated. IgG or IgM reacting with Ag present on surface of cells.
=> complement or FcR on macrophages
=> opsonisation of targt cells

*IgM associated with antigens

Question 7

Illustrate the clinical effects of Type II hypersensitivity.

Answer 7

=> immune mediated haemolysis
=> drug-induced haemolysis

Question 8

Define the pathophysiology of immune complex formation in localised and systemic Type III hypersensitivity.

Answer 8

Immune-complex, IgG also responsible
=> dmg caused by ag-ab complex whcih circulate
=> innate immun activation = mast cell, thrombi, capillary permeability

*usually will be cleared by complement = phagocytosis

Question 9

Explain the factors involved in formation of abnormal immune complexes.

Answer 9

polvalent antigens, and creation of large complexes that circulate and initiate innate immunity

• drugs eg. vaccines
  *

Question 10

Illustrate the clinical effects of Type III hypersensitivity.

Answer 10

glomerulonephritis, SLE, arthus reaction, farmer’s lung

Question 11

Define the roles of haptens, carrier proteins, Th1 cells, Th17 cells, antigen presenting cells and monocytes/macrophages in Type IV hypersensitivity.

Answer 11

Slowest, delayed response mediated by T cells

*dendritic cells present antigens in LN presenting to Tc.
* Proliferaation of specific Tc which migrate to site of inflammation
* TNF secreted by macrophages and Tc stimulate draamage

Th1 and Th17 infiltrate synovium (RhArth.) or produce inflammatory lesions in NS (MS)

> avoid antigen triggers
anti-inflamm: NSAIDs, steroids, TNF-blockers, IL-6 blocker, Ab against B cells
imm. suppr.

Question 12

Illustrate the clinical effects of Type IV hypersensitivity.

Answer 12

rheumatoid arth.,
- joints, tendons
- citrullinated proteins = ag drive.
= anti-CCP antibodies

+osteoclast activation
+ persistent IL-6 = acute phase reponse
+ smoker associated, porphyromonas infection (gum infection)

MS.
- inflamm. lesions = relapse-remitting nature
= myelin loss/time

T cells in plaques react to protein

Question 13

Antibody associated with different hypersensitive conditons

Answer 13

IgE, it may subsequently trigger immediate hypersensitivity, which manifests as allergy symptoms such as asthma or rhinitis.

dust stimulates IgG antibodies, it may trigger a different kind of hypersensitivity, such as farmer’s lung.

Question 14

Define hapten

Answer 14

Haptens are small molecule irritants that bind to proteins and elicit an immune response.

Question 15

Mechanism of corticosteroids in the therapy of atopic disease

Answer 15

inhibit the synth of MC mediators.

+similarly, epinephrine, and SABA inhibt the effects of MC mediators also.

Question 16

Alloimmune haemolysis

Answer 16

IgG = rhesus antigen

=> incompatibility illicited from prior exposure, and hemolysis occurring at the second pregnancy.

Question 17

Autoimmune mediated hemolysis

Answer 17

AuImm:
- induced by infection, drugs
- SLE
- autoantibodies produced by malgnant b cells

Type II AuImm Solid Tissue:
- goodpasture syndrome IgG = basement membrane of lung and glomeruli.
anti-basement membrane elicits complement = immune response

Question 18

Graves Disease

Answer 18

hyperthyroidism = young women, fh dt stimulation of THS receptor

Question 19

Define the mechanisms by which immunological tolerance arises.

Answer 19

*same ag may induce imm response or tolerance depending on environmental conditions and other stimuli

TOLEROGENS = ag inducing tolerance
- self-tolerance arises from elimination of self-reaactive T and B cells
* central and peripheral toleran e

AUIMM arises from failure of self-tolerance

Question 20

Define Autoimmune Disease.

Answer 20

adaptive immune response to self-ag, facilitated by autoantibodies

*autoractive T cells or AuAb facilitate tissue damage via type II, III, IV sensitivity

Question 21

Illustrate the factors involved in the aetiology of autoimmune disease.

Answer 21

genetic predisposition: poor HLA binding for self-ag, poor expression of self-ag in thymus
- polymorphism clusters in families implicated in breakdown of tolerance

infective:
- molecular mimicry

environmental factors: free radicals, radiation = alter self-peptide
- UV radiation - skin inflamm.

Question 22

Describe the pathogenetic mechanisms involved in autoimmune disease.

Answer 22

breakdown at diffent points of maintenance
- disrupted self-ag presentation at thymus

• less autoreactive t cells deleted = more escape to periphery
• leaked dna not cleared by complement: SLE has DNA-IgG complexes
• physical barriers around cells defective
• infection may trigger molecular mimicry

Question 23

Contrast organ-specific and non-organ specific autoimmune disease.

Answer 23

NON-ORGAN-SPECIFIC => affect multiple organs dt wide distirbution of responses against self-molecules
- SLE
- RhArth.
- Dematomyositis

ORGAN-SPEC => restricted to one organ, endocrine glands (T1DM)
- MS
- Hashimotos & other thyroid etc.
- MGravis
- Pernicious anemeia
- Addisons
- Pancreeas

Question 24

Define the role of HLA molecules in autoimmune disease.

Answer 24

The human leukocyte antigen (HLA) system, which corresponds to the major histocompatibility complex (MHC) in humans, plays a pivotal role in the antigen presentation of intracellular and extracellular peptides and the regulation of innate and adaptive immune responses

he development of protease inhibitors designed to alter the antigen presenting properties of HLA molecules, by blocking the presentation of potentially auto-antigenic peptides, could direct the immune system away from a particular antigenic motif and in turn the autoimmune disease process

Question 25

Central Tolerance Vs Peripheral Tolerance

Answer 25

CENTRAL TOLERANCE
- thymus: elimates T cells with high affinity to self-ag
- bone marrow: B cell tolerance

PERIPHERAL TOLERANCE
- mature lymphocytes recognise self-ag in periphery become incapable of activation or are destroyed via apoptosis
via
* anergy
* antigen recognition without co-stim.
* Treg suppression
* deletion
* sequestration

Question 26

Natural Ab

Answer 26

Present and produced without Tcells.
- bind invading gut
- bind dna released from debris and apoptosis
- bind A or B ag on red cells

Question 27

Molecular Mimicry - Infective Associations

Answer 27

GroupAStrep (GAS) = mimicry with ag found in cardiac muscle dt RHEUMATIC FEVER

Caampylobactr jejuni = mimicry with myelin proteins dt GUILLAIN BARRE SYNDROME

Question 28

SLE

Answer 28

HLA-DR2 association & impaired DNA clearance = DNA-T escape

+ drugs, UV, pregnancy => DNA/antibody complexes

Question 29

Define Primary & Secondary Immune Deficiency

Answer 29

1º = Intrinsic defect in the immune system.
*congenital, missing enzyme / physiological aspect etc.

2º = To a known condition, toxins or drugs-acquired.
* lymphoid malignancy, infection, imm suppr drugs.

Question 30

Explain the classification or primary immune deficiency disorder

Answer 30

ADAPTIVE DISORDERS
B-cells: CVID, XLA
* Common Variable Immune Deficiency (CVID) commonest dx.

T-cells: AIRE mutation

Combined: Wiskott-Aldrich syndrome, DiGeorge, Ataxia Telangiectasia

INNATE IMMUNITY
Phagocytic defect: chronic granulomatous disease
Complement defects

IMMUNE DYSREGULATION DISORDER: HLF, ALPS, IPEX, APECED

Question 31

Give examples of primary disorder of T cell, B cell, phagocyte & complement function

Answer 31

B CELL: Bruton’s Doisease, hyperIgM,

Question 32

Illustrate the complication of immune deficiency disorders.

Answer 32

upper and lower tract infections

GI disease: giarda, bacterial overgrowth, etc.
*Echovirus infection in XLA and CVID

+Arthropathy
+ AuImm phenomenon
+ malignant disease (lymphoid origin)

Question 33

Common Variable Immune Deficiency (CVID)

Answer 33

commonest form of primary antibody deficiency
* low IgG & IgA serum, with normal/reduced IgM/B cells
* dysfunctional cell mediaated immunity as well

Question 34

AIRE mutation

Answer 34

mucocutaneous candidiasis (thrush) and autoimmune endocrinopathy

• AIRE gene = expression of tissue specific self-ag thus aan autoimm regulator

Question 35

SCID

Answer 35

failure of B and T function: variance dependent on present T, B, and NK cells

• infants presenting with chronic/persistent infection and failure to thrive

> BM transplant; or haematopoietic stem cell transplantation

Question 36

Deficiencies in Innate Immunity

Answer 36

MACROPHAGE DEF.

NEUTROPHIL DEF.
* chronic granulomatous disease

COMPLEMENT DEF.

Question 37

Significance of blood transfusion reaction and IgA deficient patients

Answer 37

CVID for example, will have a higher risk of an adverse reaction

Question 38

DiGeorge Inheritance Pattern

Answer 38

AuDom 22q11.2 microdeletion