Immunology

Question 1

Innate Immunity - cells responsible for innate immunity

Answer 1

macrophage - phagocytosis and activation of bactericidal mechanisms, antigen presentation

neutrophil - phagocytosis and activation of bactericidal mechanisms

mast cells - ease of granules containing histamine and other active agents

NK cells - release lytic granules that kill some virus-infected cells, through recognition by downregulation of MHC-I

Question 2

Sequence of Acute Inflammation

Answer 2

1. tissue damage causes release of vasoactive and chemotactic factors that trigger a local increase in blood flow and capillary permeability 2. permeable capillaries allow influx of fluid (exudate) and cells 3. phagocytes migrate to site of inflammation 4. phagocytes and antibacterial exudate destroy bacteria

Question 3

Phagocytes in the body

Answer 3

brain - microglia

lungs - alveolar macrophages

liver - kuppfer cells

blood and bone marrow - macrophages

kidneys - mesangial phagocytes

skin and mucosa - langerhans cells

Question 4

macrophage activation

Answer 4

releases cytokines IL-1, 6, 8, 12 and TNF-alpha.

Question 5

Cytokines released by T-cells

Answer 5

All T cells - IL-2 and IL-3

Th1 - IF-gamma

Th2 - IL-4, IL-5, IL-10

Question 6

Functions of Interleukins

Answer 6

[Hot T-bone stEAK]
IL-1: fever
IL-2: stimulates T cells
IL-3: stimulates bone marrow
IL-4: stimulates IgE production
IL-5: stimulates IgA production
IL-6: stimulates aKute-phase protein production

IL-8: Major chemotactic factor for neutrophils
(Clean up on aisle 8)

IL-12: Activates NK cells and induces differentiation of CD4 cells into Th1

Question 7

Function of Interferons

Answer 7

IFN-alpha/IFN-beta: Part of innate response, INTERFERE with viruses, causing apoptosis

IFN-gamma: Secreted by NK cells in response to IL-12. Activates other NK cells and macrophages to kill. Increases MHC expression and antigen presentation by all cells.

Question 8

Complement

Answer 8

A series of 20 plasma proteins activated by foreign cells or antibodies to those cells. They lyse bacteria, promote phagocytosis, and promote inflammation.

Question 9

Opsonins

Answer 9

Proteins that coat pathogens so phagocytes recognize and ingest them. These could be antibodies, acute phase proteins, and complement proteins.

Question 10

Acute phase response

Answer 10

Refers to the response of the liver to inflammation. Is triggered by the release of TNF-alpha, IL1, IL6, and IL8 from neutrophils and macrophages. Liver produces acute-phase reactants, most notably C-reactive protein, to support the immune system in many ways. Major component of innate immune response.

Question 11

Eosinophils

Answer 11

Phagocytic, primary cell involved in allergic and parasitic invasion. Stimulate histamine release from mast cells and basophils.

Question 12

Mast cells and basophils

Answer 12

Immune cells that function to detect foreign substances in tissue spaces; initate local inflammatory responses

Mast cells: Bound IgE stimulates degranulation & release of mediators -> immediate hypersensitivity (allergic rxn). Mast cells release: Activators (vasodilation and vascular permeability), spasmogens (bronchial smooth muscle contraction), and chemoattractants (e.g. cytokines).

Question 13

T Cells

Answer 13

Cells that recognise processed antigens,

Created in bone marrow, matures in thymus

T-cytotoxic cells - CD8+, MHCII

T-helper cells - CD4+, MHCI

Th1 - Maximizes the killing efficacy of the macrophages and the proliferation of cytotoxic CD8+ T cells. Also promotes the production of opsonizing antibodies. (IgG, IgM and IgA, not IgE)

Th2 - Stimulates B-cells into proliferation, to induce B-cell antibody class switching, and to increase neutralizing antibody production. (IgG, IgM, IgA and IgE)

Question 14

MHC I

Answer 14

A, B, and C types, with further subtypes. Displays peptides from intracellular proteins. Recognized by CD8 T cells. Expressed by all nucleated cells.

Cytoplasmic proteins are broken down by the proteasome complex, peptides exported to the ER, bound to MHC I, then MHC I with peptide is transported to the cell surface. (Attached within ER)

Question 15

MHC II

Answer 15

DR, DP, DQ types, with further subtypes. Displays peptides from extracellular proteins. Recognized by CD4 T cells. Only expressed by professional APCs.

Exogenous proteins are taken up by endocytotic processes, degraded by proteases within uptake vesicles, bound to MHC II, then displayed at the cell
surface. (Attached outside of ER, remains in vesicle)

Question 16

Immunoglobulin structure

Answer 16

Inner heavy chain, outer light chain, linked by disulphide bonds in the hinge region. The Fc domain contains the C terminus of the heavy chain and is either attached to the B cell or freely floating. The Fab domain contains the N terminus, consists of both chains, and is termed the “variable region”.

Question 17

Immunoglobulin function

Answer 17

Neutralization, opsonization, and antibody-dependent cell mediated cytotoxicity (ADCC) on NK cells

IgG - Most common (75%), found in serum/tissue fluids, produced in secondary immune response, can cross placenta and provide passive immunity to newborns

IgM - Primary immnue response Ig, mainly confined to vascular pool, binds with low affinity and high avidity due to pentameric structure, potent activator of complement pathway. multimeric

IgD - Most obscure Ig, no known functions, found on surface of new B cells

IgA - Functions as a neutralizing antibody, found in the gut and secreted fluids, usually occurs as a dimer with a secretory component that is synthesized by epithelial cells, can be transported across epithelial surfaces. multimeric

IgE - Located along blood vessels and just beneath epithelial surfaces, binds to mast cells via Fc receptors and cross linking upon second exposure leads to allergic response

Question 18

Function of dendritic cells

Answer 18

Reside in tissues, capture antigens and move to lymph nodes upon activation via PAMP receptors, present MHC II/peptide complex to naive T cells

Question 19

Reason for Ig diversity

Answer 19

1. Somatic recombination of VDJ gene segments
2. Pairing of heavy and light chains
3. Somatic hypermutation
4. Junctional diversity

Question 20

X-linked agammaglobulinemia

Answer 20

epidemiology: 1:250,000 in population, only male, usually appears 4-5 months

Aetiology/pathophys: Absence of BTK gene, B cells can’t differentiate

Diagnosis: No class of antibodies present, absence/reduction of spleen, tonsils, adenoids, peripheral lymph nodes

Confirmed from abnormally low or absent B cells, T cell count may be elevated.

Clinical features/consequence: Recurrent infections, diarrhoea, staph

Treatment: No cure, commonly treated with IVIg, antibiotic therapy and nutritional supplements

Question 21

Severe combined immune deficiency (SCID)

Answer 21

Epidemiology: Aus 0.15:100,000 incidence. X-linked males only, autosomal recessive males and females equally. patients present around 3mth, age at diagnosis 6mth

Aetiology/pathophys: Mutation of common Y chain of IL receptors encoded on X chromosome - X-linked

adenosine deaminase deficiency builds up enzymes, inhibits lymphocyte proliferation - autosomal recessive

Clinical features: Profound abnormalities in T-cell, B-cell and NK cell functions, paediatric emergency. FTT, multiple and severe recurrent infections (particularly resp)

Diagnosis: clinical features + fever, dehydration, increased RR, absent lymphatic tissue. Hallmark = lymphopenia

CBC, total serum Ig levels, lymphocyte count and function

Consequences: severe opportunistic infection with viral, fungal and bacterial sources. If not treated = death

Treatment: IVIg, Bone marrow transplant, gene therapy

Question 22

DiGeorge Syndrome

Answer 22

Epidemiology: 1:4000-6000, sexes equally affected, no ethnic predisposition, detected in infancy but late presentation is possible

Aetiology/pathophys: parents with DGS, deletion of one copy of 22q11.2 causes decreased levels of TBX1 which is a key transcription factor for development of pharyngeal arches. No thymus - failed T cell maturation

Clinical features: hypoplastic/absent thymus and parathyroid glands. T cell deficiency, cleft lip and palate, mild dysmorphic facial features, cardiac anomalies (truncus arterioles, Tetralogy of fallot)

Diagnosis: abnormal T cell cound, low serum calcium, low serum Ig, abnormal CXR and ECG. fluorescence in situ hybridisation to confirm DGS

Consequences: long term heart defect, increased risk sinopulmonary infections, risk schizophrenia

Treatment: IVIg, thymic transplant, adoptive transfer of mature T cells

Question 23

Common Variable Immune Deficiency (CVID)

Answer 23

epidemiology: 1:50,000. 1M:1F. can become evident any time 0-40yrs

Aetiology/pathophys: Lack of B cells (failed development), defect in B-cell expression in surface molecules, defecits in second messenger and translocation pathways in B cells

Clinical features: low levels of most/all Igs, lack of B cells and plasma cells capable to produce Igs, frequent bacterial infections, splenomegaly, lymphadenopathy

Diagnosis: decreased/absent IgA and IgD, decreased IgM, test for circulating T and B cell function

Consequences: recurrent infections, auto-immune phenomena, possible malignancy.

Treatment: IVIg

Question 24

Chronic Granulomatous Disease

Answer 24

Epidemiology: usually inherited in x-linked recessive, 90% males, 1:160,000-1,000,000. Typically occurs at a young age, may have late onset

Aetiology/pathophys: Impaired phagocyte function. Defects in NADPH oxidase enzyme complex that generates ‘respiratory burst’. Inability of phagocytes to kill

Clinical features: recurrent bacterial and fungal infections, skin infections, pneumonia, spleen/liver/gingival abscesses, granulomas

Diagnosis: nitroblue tetrazolium test - in CGD, patients are unable to oxidise NBT to insoluble blue formazan. Dihydrorhodamine test: principles are similar to NBT. CBC: anemia, high level of circulating neutrophils. Quantitative Ig test: all increased

Consequences: intracellular survival of ingested bacteria leads to granuloma formation in lymph nodes, skin, lungs, liver, GIT and bones

Treatment: aggressive and prolonged broad-spectrum antibiotic therapy, antifungal therapy, bone marrow transplant or haemopoietic stem cell transplant may be successful