Immunology

Question 1

Define innate immunity and recall the host-microbe interactions

Answer 1

Innate immunity:

• First line (and second line) of defence against invading pathogens
  
  • First line: skin, mucous membranes, secretions of skin and mucous membranes
  • Second line: phagocytic leukocytes, antimicrobial proteins, inflammatory response
• Can activate acquired immune system
• Ability to differentiate between host and pathogen (e.g. sentinel cells in stratum spinosum)

Host-microbe interactions – (bacterial) infection pyramid:

Question 2

List the main functions of the innate immune system (5 points)

Answer 2

Functions of innate immune system:

1. Anatomic and physiologic barriers
2. Phagocytosis
3. Activation of acquired immune system
4. Immune cell recruitment
5. Completement activation

Question 3

List the anatomic and physiologic barriers of the innate immune system

Answer 3

Anatomic and physiologic barriers of innate immune system:

“_S_avage _M_ermaids _S_mash _T_urtles”

• Skin – physical barrier; tight junctions in epithelium; desquamation to remove adhered pathogens
• Mucous membranes – resp. and GI tracts; slimy surface traps pathogens, ciliary clearance; defensins
• Secretions – stomach acid, digestive enzymes, tears (lysozyme), mucous, sweat
• Temperature – Normal body temperature and/or fever inhibits growth of some pathogens.

Question 4

Describe the function of defensins in the innate immune system

Answer 4

Defensins:

• Contained in mucous membranes of all animal and plant cells
• Short, +ve charge (cationic) proteins, with hydrophobic and amphiphilic domains
• Abundant in neutrophils (to kill phagocytosed pathogens)
• Broad spectrum of antimicrobial activity (Gram +ve/-ve bacteria, fungi, parasites, enveloped viruses).
• Difficult for microbes to acquire resistance to defensins.

Question 5

What is the overall host response to injury or infection?

Answer 5

Host response to injury or infection – the inflammatory response.

Inflammatory response has two main immunological components:

1. Innate, non-adaptive response (non-specific)
2. Acquired, adaptive response (specific response)

Question 6

Outline the stages of the innate immune response against injury or infection

Answer 6

Stages of the innate immune response:

• Occurs immediately on injury or infection
• Comprises vascular and cellular changes
• PRRs on sentinel cells detect PAMPs on pathogens – triggers cytokine release (IL-1, TNF-α):
  
  • vasodilatation
  • expression of adhesion molecules on cell surfaces
• Leukocytes roll on, adhere to and migrate through activated vascular endothelium towards pathogen
• Phagocyte (leukocyte) and NK cell (lymphocyte) activity
• Complement system activation (end result is cell lysis via MAC complex)
• Activation of acquired immune response

Question 7

Describe and explain the role of pathogen associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs)

Answer 7

Recognizing a pathogen – PAMPs and PRRs

Pathogen associated molecular patterns (PAMPs):

• Microorganism surface components
  
  • Peptidoglycan cell wall
  • Flagella of bacteria
  • Lipopolysaccharide (LPS) on Gram -ve bacteria
  • Teichoic acids on Gram +ve bacteria
  • Molecules in the cell walls of fungi (zymosan, glucan, chitin)
• Short bacterial DNA sequences (CpG motif – twenty times less common in vertebrate DNA than in bacterial DNA)

PAMPs are specific to pathogens (pathogen-associated) and enables the immune system to distinguish self from non-self via host pattern recognition receptors.

Patten recognition receptors (PRRs)

• Soluble receptors in cytoplasm:
  
  • NOD-like receptors (NLRs)
  • RIG-I-like receptors (RLRs)
• Membrane-bound receptors:
  
  • Toll like receptors (TLRs)
  • C-type lectin receptors (CLRs)

Question 8

Recall the 6 main outcomes TLR stimulation

Answer 8

Question 9

Which TLRs recognize bacterial lipids?

Answer 9

11 families in mammals (TLR 1–11):

TLR 1, 2, 4, and 6 recognize bacterial lipids

Question 10

Which TLRs reconize viral RNA?

Answer 10

TLR 3, 7, and 8 recognize viral RNA

Question 11

Which TLRs recognize bacterial DNA?

Answer 11

11 families in mammals (TLR 1–11):

TLR 9 recognizes bacterial DNA

Question 12

Which TLRs recognize bacterial and parasite proteins?

Answer 12

11 families in mammals (TLR 1–11):

TLR 5 and 10 recognize bacterial and parasite proteins

Question 13

Which TLRs are present on the cell surface?

Which TLRs are intracellular?

Answer 13

Cell surface: TLR 1, 2, 4, 5, 6, and 10

Intracellular: TLR 3, 7, 8, 9, and 11

Question 14

Describe the stages involved in phagocytosis (7 points)

Answer 14

Stages of phagocytosis:

1. Binding of opsonins (complement or antibody) to pathogen (or antigen presenting cell)
2. Phagocyte recognizes opsonin +/- PAMPs of pathogen
3. Cell membrane of phagocyte extends and envelops opsonized target
4. Pinches off in cell cytoplasm to form a phagosome
5. Phagosome fuses with lysosome to form phagolysosome
6. Lysosomal enzymes digests contents
7. Release of digestion products from cell

TLR-mediated signalling pathways lead to the translocation of transcription factors that activate the elements of immune response

Question 15

List 3 types of phagocyte

Answer 15

Phagocyte:

1. Monocytes
   
   • Dendritic cell
   • Macrophage (Mφ)
2. Neutrophil
3. Mast cell

Question 16

List the 3 distinctive pathways of the complement system

Answer 16

Distinct pathways of the complement system (3 points):

1. Classical pathway (Ag-Ab)
2. Lectin pathway (microbial carbohydrates: MBL, MASP-1, -2)
3. Alternative pathway (spontaneous, activating surfaces)

All meet at level of C3 convertase which reacts with C5 to produce membrane attack complex (MAC)

Question 17

Describe the action of natural killer cell (NK cell)

Answer 17

NK cells cause lysis of targets cells via induction of apoptotic or necrotic pathways

Action of NK cell depends on balance of activating and inhibitory signals via receptors on NK cell:

• Activating receptors recognize molecules that are expressed on the surface on cancer cells and infected cells, and ‘switch on’ the NK cell
• Inhibitory receptors on the surface of NK cell recognize cognate MHC I (found on normal healthy cells), and this ‘switches off’ the NK cells, prevent it from killing.

Question 18

Recall the mechanism of action of NK cell (4 points)

Answer 18

Cancer cells and infected cells often lose their cell surface MHC I, leaving them vulnerable to NK cell killing (since MHC I normally inhibits NK cells).

Mechanism of action of NK cell (4 points):

1. NK cell releases cytotoxic granules containing perforin and granzymes
2. Perforin creates pore in cell membrane of target cell (e.g. pathogen, tumor)
3. Granzymes enter cell cytoplasm
4. Granzymes induce apoptosis

Question 19

Define acquired immunity

Answer 19

Acquired, adaptive immune response (specific response):

• Immunity that an organism develops during lifetime – after exposure to antigens
• Involves activity of lymphocytes
• Includes 3^rd line of defence (1^st and 2^nd line involved in the innate, non-specific immune response)

Question 20

Recall the different types of passive vs active acquired immunity

Answer 20

Acquired immunity may be acquired either actively or passively:

Question 21

List the 4 key attributes of acquired immune response

Answer 21

Acquired immune response exhibits 4 immunologic attributes:

1. Specificity
2. Diversity
3. Memory
4. Self/non-self recognition

Question 22

Explain why acquired immunity elicits a specific, later response than innate immunity

Answer 22

The acquired immune response is slower-acting, longer-lasting, and more specific than the innate immune response:

• The acquired immune response occurs in two phases: the induction phase and effector phase
• The acquired immune response first requires signalling from the innate immune response to function
  
  • Antigen presenting cells (APCs) of the innate immune system, e.g. macrophages and dendritic cells, display antigens via MHC molecules to complementary naïve T lymphocytes e.g. CD4+ (MHC II) or CD8+ (MHC I), of the acquired immune system.
• In response, the T lymphocytes need time to differentiate and proliferate into T_H cells or T_c cells (i.e. the induction phase).

Therefore, the process of responding to the APCs of the innate immune system takes time because it involves protein synthesis and cell division, but lasts much longer and has greater specificity.

Question 23

Which lymphocytes are involved in cell-mediated immunity?

Which lymphocytes are involved in antibody-mediated immunity?

Answer 23

T lymphocytes – involved in cell-mediated immunity (i.e. cellular immunity)

B lymphocytes – involved in antibody-mediated immunity (i.e. humoral immunity)

Question 24

Describe the key features and functions T lymphocytes:

1. Expression of cell surface receptors and secretion of proteins
2. Structure of cell surface receptors and secretion of proteins
3. Diversity of cell surface receptors and secretion of proteins

Answer 24

T lymphocytes (matured in the thymus):

• T cell receptor (TCR) – protein complex which detects antigen bound to MHC I or MHC II:
  
  • Class I MHC proteins – found on virtually all body cells (including cancer cells)
  • Class II MHC proteins – found on certain cells in the immune response (APCs)
• T lymphocyte types (diversity):
  
  • Helper T cell (T_H) – secrete cytokines to help B cells and T_c cells to divide
  • Cytotoxic T cells (T­_c , or killer T cells) – kill infected body cells
  • Memory T cells (MT) – remain in the body in case of subsequent exposure to antigen.

Question 25

**Described the key features and functions B lymphocytes:** 1. **Expression of cell surface receptors and secretion of proteins** 2. **Structure of cell surface receptors and secretion of proteins** 3. **Diversity of cell surface receptors and secretion of proteins**

Answer 25

B lymphocytes (matured in the **_b_**one marrow): * B cell receptor (BCR) – antibodies (i.e. immunoglobulins, Ig) can detect extracellular antigens * IgD is the antibody specific to B lymphocytes (B cell activation, can’t cross placenta) * Behave directly as APCs, and differentiate into plasma cells (release Ab) and memory B cells (MB). * B lymphocyte types (diversity): * B cell which differentiates into plasma cells (release antibodies) * B cell which differentiates into memory B cells (MB cells) which remain in the body in case of subsequent antigen exposure.

Question 26

**Explain the role of B lymphocytes in humoral immunity**

Answer 26

Antibody-mediated (humoral) immunity: * Target _extracellular_ microorganisms (bacteria and viruses circulating in blood) * T_H cells stimulate B cells that have engulfed and presented pathogen-derived antigens. * B cells differentiate into plasma cells that secrete antibodies.

Question 27

**Identify the immunoglobulin classes (IgG, IgA, IgM, IgD, IgE) and their functions**

Answer 27

Question 28

**Explain the nature of immunoglobulin-antigen binding**

Answer 28

Immunoglobulin (antibody) nature: * 2 variable ‘arms’ regions specifically for antigen binding (antigen-binding fragment, Fab) * 1 constant ‘tail’ region specifically for cells of immune system (constant fragment, Fc). 'Y-shape' Ig

Question 29

**Differentiate between the primary and secondary phases of the humoral immune response (8 step explanation)**

Answer 29

1. First ever exposure to antigen (e.g. pathogen): innate immune system recognizes antigen as foreign (sentinel cell phagocytoses pathogen, presents antigen protein fragments – now considered APC). 2. APC interacts with CD4+ and CD8+ T lymphocytes via the APC’s MHC I and MHC II surface proteins, respectively. Induction phase begins: 3. CD4+ and MHC II interaction initiates T_H cell proliferation and B cell proliferation (humoral response) 4. CD8+ and MHC I interaction initiates proliferation of T_c cell proliferation (cellular response) 5. Predominant antibody type in primary response to first ever antigen exposure: IgM (pentameric) 6. Both interactions also produce memory T cells and memory B cells ready for subsequent exposure 7. Subsequent exposure to the same antigen initiates a more rapid secondary response (since there is no need for innate immune response) through activation of memory B cells (act directly as APC) and T cells into effector cells. 8. Predominant antibody type in secondary response: IgG (monomeric)

Question 30

**Explain how immunoglobulins (antibodies) protect against infectious agents, including:** 1. **Neutralisation** 2. **Agglutination** 3. **Opsonisation** 4. **Activation of complement** 5. **Antibody-dependent cell-mediated cytotoxicity**

Answer 30

Neutralization – antibodies block the activity of the pathogen by saturating pathogen’s cell surface antigens. Agglutination – multiple pathogens are aggregated by antibody molecules (macrophages then phagocytose). Opsonization – pathogens bound by antibodies are more efficiently engulfed by phagocytes (free Fc region). Activation of complement – antibodies bound to pathogens activate the complement cascade (free C1 protein binds to F_c region of antibody) Antibody-dependent cell-mediated cytotoxicity – abnormal body cells that are bound by antibodies are recognized by NK cells and are subsequently lysed (free Fc region).

Question 31

**Describe the three complement pathways (classical, alternative and lectin)**

Answer 31

Classical pathway: * Ag-Ab complex on pathogen surface (C1q,r,s) MB-Lectin pathway: * Mannose-binding lectin binds mannose (sugar monomer) on pathogen surface Alternative pathway: * Spontaneous hydrolysis of C3-H₂O

Question 32

**Describe the extracellular (exogenous) antigen processing pathway by APCs (4 points)**

Answer 32

Extracellular (exogenous) antigen processing by APC: 1. Exogenous antigen is ingested by phagocytosis (trapped inside intracellular phagosome) 2. Phagosome combines with lysosome to form phagolysosome (contains lysozymes) 3. Lysozymes and acidic environment of phagolysosome degrade antigen into small peptides 4. Small peptides are then presented with class II MHC molecules on cell membrane of APC.

Question 33

**Describe the intracellular (endogenous) antigen processing pathway by APCs (4 points)**

Answer 33

Intracellular (endogenous) antigen processing by APC (4 points): 1. Endogenous antigen is produced inside the cell itself (e.g., in a virus-infected cell) 2. Antigen is degraded within the cell cytoplasm into small peptides 3. Small peptides move into endoplasmic reticulum and bind to class I MHC molecules 4. Peptide-class MHC I complexes then move through Golgi apparatus to cell membrane of APC.

Question 34

**Define major hisocompatibility complex (MHC)**

Answer 34

Major histocompatibility complex (MHC) molecules: * Major (i.e. essential) * Histo- (relating to tissues) * -Compatibility (genetic variation so different shape protein; leads to non-self rejection of tissues). Two main classes of MHC: 1. Class I MHC 2. Class II MHC

Question 35

**Explain the role of MHC molecules in adaptive immunity**

Answer 35

Class I MHC presents antigen and interacts with complementary CD8+ T lymphocytes * MHC I-TCR complex is stabilized by CD8+ peptide (co-receptor) to allow for IL-1, -2 signalling * Initiates cell-mediated immune response (proliferation of T_{c ­­}cells) Class II MHC presents antigen and interacts with complementary CD4+ T lymphocytes * MHC II-TCR complex is stabilized by CD4+ peptide (co-receptor) to allow for IL-1, -2 signalling * Initiates cell-mediated (proliferation of T_H cells, T_reg cells) and antibody-mediated immune response (proliferation of B cells then differentiation into plasma cells)

Question 36

**Explain how helper, cytotoxic and regulatory T cells contribute to cell-mediated immunity**

Answer 36

Cell-mediated immunity (immune response towards infected cells, cancer cells and transplant cells): * Helper T cells – secrete cytokines and help B cells and T_c cells to divide * Cytotoxic T cells – kill infected body cells by perforin and granzyme action * Regulatory T cells – restrain and inhibit the cell-mediated response to prevent excessive reaction and autoimmunity

Question 37

**Explain how helper T cells regulate the immune system**

Answer 37

Helper T cells (T_H): * Bind to other white blood cells that have previously encountered an antigen and release cytokines: * Stimulate proliferation of other T cells * Stimulate B cells that have already become bound to antigen * Without T_H cells there is no immune response

Question 38

**Explain the function of cytotoxic T cells**

Answer 38

Cytotoxic T cell (T_c): * Destroys infected body cells * binds to target cell * secretes perforin protein (punctures cell membrane) and granzymes (induces apoptosis).

Question 39

**Describe the role of regulatory T cells**

Answer 39

Two main types of regulatory T cells: 1. Inducible regulatory T cells (iT_reg) are derived from T helper cells precursor (T_H0) 2. Naturally occurring regulatory T cells (nT_reg) are matured in the thymus Regulatory T cells restrain and inhibit the development of the immune response, preventing autoimmunity and excessive immune activation.

Question 40

**Recall the overall picture of the innate and adpative immune responses**

Answer 40

Question 41

**List the 3 basic layers of the mucosa**

Answer 41

Mucosa made up of 3 basic layers: 1. Epithelial lining (innermost, luminal aspect) 2. Lamina propria (cellular connective tissue deep to epithelial layer, e.g. lymphocytes) 3. Muscularis mucosae (deepest aspect of mucosa; enables peristalsis of mucosa)

Question 42

**Summarize the lymphatic system**

Answer 42

The lyphatic system: 1. The immune system is _organised into several specialized tissues_ which are collectively termed as _lymphoid or immune tissues_ 2. Tissues that have _evolved to a high degree of specificity of function_ are termed as _lymphoid organs_ 3. Organs of the immune system have been divided into: * _Primary_ lymphoid tissue * _Secondary_ lymphoid tissue

Question 43

**List the 2 primary (central) lymphoid tissues**

Answer 43

Primary (central) lymphoid tissues: 1. Bone marrow 2. Thymus

Question 44

**List the 3 secondary (peripheral) lymphoid tissues**

Answer 44

Secondary (peripheral) lymphoid tissues: 1. Lymph nodes 2. Spleen 3. MALT

Question 45

**Describe the structure of lymph nodes (5 points)**

Answer 45

Structure of lymph node (5 points): Surrounded by a _fibrous capsule_ from which trabeculae penetrates the nodes 1. _Outer cortex_ – accumulation of lymphocytes (primary lymphoid follicles) within which germinal centres (secondary follicles) develop during antigenic stimulation. Follicle also contain dendritic macrophages. 2. _Inner medulla_ – lymphocytes, plasma cells and macrophages are arranged as elongated branching bands (medullary cords). 3. _Bursa dependent areas_ – the cortical follicles and medullary cords that contain B-lymphocytes. 4. _Thymus dependent area_ – between the cortical follicles and medullary cords there is an ill-defined intermediate zone (paracortical area) which contains T lymphocytes.

Question 46

**List the key functions of lymph nodes (4 points)**

Answer 46

Functions of lymph node: 1. Filter for lymph, each group draining specific part of the body. 2. Phagocytose foreign materials including microorganisms. 3. Help in proliferation and circulation of T cells and B cells. 4. They enlarge during local antigenic stimulation.

Question 47

**Describe the structure of the spleen**

Answer 47

Structure of the spleen _Largest lymphoid organ_ which has a _capsule from which trabeculae descend_, dividing the organ into several interconnected compartments. The spleen contains two main tissue types: white pulp and red pulp. 1. White pulp – lymphatic tissue (material which is part of the immune system) mainly made up of _white blood cells_, constitute 75% of the organ. 2. Red pulp – made up of blood-filled cavities (venous sinuses) and splenic cords. Splenic cords are special tissues which contain different types of red and white blood cells.

Question 48

**List the key functions of the spleen (4 points)**

Answer 48

Key functions of the spleen: 1. Filtering and clearing of infectious organisms. 2. Serves as a ‘graveyard’ for affected blood cells􀍘 3. Reserve tank/settling bed for blood & systemic filter to trap circulating blood-borne foreign particles. 4. The immunological function of spleen is primarily directed against blood-borne antigens.

Question 49

**Identify the 4 types of mucosa-associated lymphoid tissue (MALT)**

Answer 49

Mucosa-associated lymphoid tissue (MALT) includes 4 types: 1. Gut-associated lymphoid tissue (GALT) * Peyer’s patches (PP) * Mesenteric lymph nodes (MLN) * Appendix * Solitary lymphoid nodes 2. Nasopharyngeal-associated lymphoid tissue (NALT) * Salivary glands * Tonsils 3. Bronchus-associated lymphoid tissue (BALT) 4. Urogenital

Question 50

**Describe the structure-to-function relationship of MALT**

Answer 50

Structure of MALT: * MALT contains lymphoid as well as phagocytic cells * Both B and T cells are present * Predominant immunoglobulin produced in the mucosa is secretory IgA * Other immunoglobulin classes: IgG, IgM and IgE also formed locally. Function of MALT: * The systemic immune system – largely sterile environment. Vigorous response to microbial invasion. * In contrast, mucosal immune system – constant exposure to ingested and inhaled foreign antigens and microbes (therefore MALT functions in a non-sterile environment with high antigen load) * Human gut hosts an enormous number of commensal microorganisms (1 x 10¹⁴) * Constant exposure to food matter (potential to cause pathogenicity)

Question 51

**Describe the 5 innate immune components of MALT (specifically, GALT)**

Answer 51

Innate immunity of MALT with reference to GALT (5 components) 1. Mucosal barriers: * Glycocalyx – goblet cells produce thick mucus with IgA to trap antigens * Tight junctions – proteins: claudin, occludin (connections just below microvilli) 2. Proteolytic enzymes: * Pepsin (stomach), small intestine (trypsin, pancreatic protease) * Breakdown polypeptides into oligopeptides (\< 8–10 aa poor immunogens) 3. Antimicrobial molecules: * Lactoferrin (binds iron to inhibit bacterial growth), lysozyme (cleaves +ve cell wall) * Defensins – produced in crypt lumen (contains Paneth cells): * Human defensin 5 and 6; Human β defensin 1 and 2) 4. Intestinal commensals (vital for certain drug and dietary nutrient metabolism – Vit K and B): * Indigenous microflora promotes formation of Peyer’s patches * Expansion of intraepithelial lymphocytes populations and IgA production * Expansion of germinal centre reactions involving T cells and B cells 5. Immune cells (IgA – may be considered an innate component)

Question 52

**The acquired immune system of MALT (specifically, GALT) can be broken down into 4 main components:** * **Unique epithelium for antigen uptake** * **Unique lymphocyte/APC repertoire​** * **IgA dominated humoral response** * **The need to minimize injury to the mucosal tissue while providing protection** **​Described the** **u****nique epithelium for antigen uptake of GALT**

Answer 52

Unique epithelium for antigen uptake: * Mucosal epithelium is an easy portal of entry; specific defence mechanisms required for specialized protection of gut * Peyer’s patch samples intestinal antigens to stimulate production of its lymphocytic family to populate the epithelial lining and isolated lymphoid follicles. * Epithelium overlying Peyer’s patch composed of M cells: * Lack microvilli * No glycocalyx coating * Interacts directly with antigens in the gut (portal of entry into GALT via transcytosis) * Certain Gram -ve pathogens can invade M cells (salmonella, shigella) * Dendritic cells can extend dendrites out onto luminal aspect of gut (between lateral junction of enterocytes, not M cells) to sample for antigens and present to T and B lymphocytes.

Question 53

**The acquired immune system of MALT (specifically, GALT) can be broken down into 4 main components:** * **Unique epithelium for antigen uptake** * **Unique lymphocyte/APC repertoire​** * **IgA dominated humoral response** * **The need to minimize injury to the mucosal tissue while providing protection** **​Described the unique lymphocyte/ APC repertoire​ of GALT**

Answer 53

Unique lymphocyte/APC repertoire: * Intraepithelial lymphocytes, IEL (CD8+ cytotoxic T lymphocytes) * Limited repertoire of TCR (compared to peripheral T lymphocytes), so can recognize a limited number of antigens to prevent indiscriminate inflammation of gut * Epithelial cells of gut undergo changes due to stress from infection, damage and toxic peptides (e.g. patient in ICU) and express self-stress antigens: MIC-A, MIC-B. * NKG2D receptors on IEL bind to MIC-A, B antigens of epithelium to induce apoptosis – a local reaction to a system stress (e.g. breakdown of gut cells in patients on ICU). * Lamina propria lymphocytes (CD4+ T helper lymphocytes, macrophages, neutrophils, B cells) * Limited proliferative capacity in lamina propria * Still acts as helper cell to mount a response for B cells and T_c cells action * Mast cells (release IgE in those sensitive to antigens, e.g. corn; results in GI upset) * Dendritic cells * Primarily protects colonic (large bowel) epithelial integrity by secreting IL-22.

Question 54

**The acquired immune system of MALT (specifically, GALT) can be broken down into 4 main components:** * **Unique epithelium for antigen uptake** * **Unique lymphocyte/APC repertoire​** * **IgA-dominated humoral response** * **The need to minimize injury to the mucosal tissue while providing protection** **​Describe the IgA-dominated humoral response​ of GALT**

Answer 54

IgA-dominated humoral response: * Dimer antibody transported via endocytosis through epithelial cells (submucosa to lumen) * Three mechanisms employed by IgA for mucosal immunity: * Secreted IgA on gut surface can neutralize pathogens and toxins * IgA is able to neutralize antigens already internalized in epithelial endosomes * IgA can export toxins from lamina propria while being secreted out into lumen

Question 55

**The acquired immune system of MALT (specifically, GALT) can be broken down into 4 main components:** * **Unique epithelium for antigen uptake** * **Unique lymphocyte/APC repertoire​** * **IgA-dominated humoral response** * **The need to minimize injury to the mucosal tissue while providing protection** **​Describe the need to minimize injury to the mucosal tissue while providing protection to GALT**

Answer 55

The need to minimize injury to the mucosal tissue while providing protection: * IgA is unable to activate complement pathways via classical or alternative pathways * IgA induced IL-1 R antagonist from monocytes (downregulate mounted immune response) * Treg cells (from CD4+ cell activation) secrete IL-10 to restrain lamina propria immune cells.

Question 56

**Summarize the structure-to-function relationship of MALT (specifically, GALT)**

Answer 56

Question 57

**Define autoimmunity, autoantigens and autoantibodies**

Answer 57

Autoimmunity – disease involving the breakdown of mechanisms responsible for self-tolerance and induction of specific adaptive immune response against components of the self. Autoantigen – any antigen that stimulates antibodies in the organism that produced it. Autoantibody – antibody formed in response to an agent produced by the organism itself.

Question 58

**Classify autoimmune diseases into organ-specific and non-organ specific (systemic) and provide examples**

Answer 58

Question 59

**Described the 3 main phases of autoimmunity development**

Answer 59

Main phases of autoimmunity development (3 points): 1. Initiation phase – genetic and environment triggers; subclinical phase. 2. Propagation phase – clinical presentation, self-perpetuating inflammation and tissue damage 3. Resolution phase – activation of inhibitory pathways; relapse and remission of disease.

Question 60

**List the proposed theories (mechanisms) leading to autoimmunity (7 points)**

Answer 60

Proposed theories (mechanisms) of autoimmunity: 1. Forbidden clone theory 2. Altered antigen 3. Sequestered antigen 4. Immunologic deficiency 5. Genetic influence 6. Molecular mimicry 7. Hygiene hypothesis.

Question 61

**Describe the forbidden clone theory for autoimmune development**

Answer 61

Forbidden clone theory: * Lymphocytes mutate during maturation producing “forbidden patterns” * Forbidden patterns mount immune response to host cells.

Question 62

**Described the altered antigen theory for autoimmune development**

Answer 62

Altered antigen theory: * Environmental factors alter host cells to render them non-recognisable as self and therefore mount antibody response: * Chemical (e.g. drug) * Biological (e.g. virus) * Physical (e.g. radiation).

Question 63

**Described the sequestered antigen theory for autoimmune development**

Answer 63

Sequestered antigen theory: * Specific areas of body are immune privileged (e.g. eyes, testes, foetus) * No contact with lymphocytes during development * Damage causes exposure in later life * Host cells recognize immune privileged tissues as foreign (e.g. sympathetic ophthalmia).

Question 64

**Described the immunologic deficiency theory for autoimmune development**

Answer 64

Immunologic dificiency theory: * Mutation or loss of immunological regulatory functions, i.e. T_reg cells (either general or specific loss) so that self behaves as foreign antigen * Defects in T_reg cell activity are associated with multiple sclerosis.

Question 65

**Described the geneteic influence theory for autoimmune development**

Answer 65

Genetic influence theory: * Certain immune disorders predominate in females and families * Genetic links have occurred between diseases and inherited human leukocytes antigen (HLA) * HLA gene complex on chromosome 6 encodes proteins that make up the MHC * Predisposition to autoimmune disease due to combined effects from multiple genes coding for: * Cytokines, inhibitory T cell surface molecule, complement, TLR, apoptosis * Single gene mutation: * Fas (death receptor) – failure of apoptosis of self-reactive B and T cells results in autoimmune lymphoproliferative syndrome.

Question 66

**Described the molecular mimicry theory for autoimmune development**

Answer 66

Molecular mimicry theory: * Structural similarity between viral T cell epitopes and self-peptides lead to induction of autoaggressive T cell response.

Question 67

**Describe the hygeine hypothesis for autoimmune development**

Answer 67

Hygiene hypothesis theory: * Lack of exposure to pathogens in early childhood leads to defective development of self-tolerance * Increased susceptibility to allergy * Increased asthma rates (especially in relatively sanitary conditions of western world).

Question 68

**Describe the role of hormones in autoimmune disease**

Answer 68

Hormones and autoimmune disease: * Oestrogen may trigger AI disease by influencing gene expression and altered immune response: * Largest difference between genders is between menarche and menopause * Disorders exacerbated during pregnancy (significant hormonal changes)

Question 69

**Explain the establishment of self-tolerance (2 main types) in autoimmunity**

Answer 69

T and B lymphocyte selection pressures result in the establishment of self-tolerance. There are two main types of self-tolerance: Central tolerance – discriminates self from non-self: * Deletion of autoreactive lymphocytes during maturation in thymus and bone marrow * Induction of apoptosis * Weakly autoreactive B cells do not respond to receptor stimulation * Weakly self-recognising T cells differentiate into natural regulatory T cells (nT_reg cells). Peripheral tolerance – prevents over-reactivity * Develops after mature lymphocytes enter the peripheral tissues and lymph nodes * T_reg cells suppress circulating lymphocytes that react to self * Apoptosis following activation * Anergy (cellular inactivation due to weak activation with no co-stimulus)

Question 70

**Describe the aetiology and pathophysiology of myasthenia gravis**

Answer 70

Myasthenia gravis: Autoantibodies block nicotinic acetylcholine receptors at the neuromuscular junction in skeletal muscle * Aetiology: certain genotypes (HLA allele – DR3); thymic follicular hyperplasia (express AChR and may trigger autoantibody synthesis). * Signs and symptoms: * Muscle weakness that increases with exercises and improves on rest * Dropping eye lids * Diplopia * Oropharyngeal weakness (successive swallows become more difficult without rest) * SOB

Question 71

**Discuss the aetiology and pathophysiology of​ systemic lupus erythematosus (SLE)**

Answer 71

Systemic lupus erythematosus (SLE): Chronic multi-system disorder, most commonly affecting women during their reproductive years, characterised by presence of anti-nuclear antibodies (ANA). Immune complexes deposit in blood vessels around body, especially nephrons of kidney, digits of extremities (type 3 hypersensitivity reactions). * Aetiology: poorly understood, familial aggregation (HLA allele – DR3), drugs (e.g. sulfasalazine, carbamazepine), Epstein-Barr virus, hormonal (oestrogen) * Signs and symptoms: * Malar “butterfly” rash on face * Photosensitive rash * Nephrosis * Arthritis * Raynaud’s phenomenon * Thrombosis

Question 72

**Discuss the aetiology and pathophysiology of​ pernicious anaemia**

Answer 72

Pernicious anaemia * Aetiology: * Vitamin B12 is required for formation of red blood cells * Vitamin B12 is absorbed in terminal ileum (requires intrinsic factor, IF) * IF is secreted from parietal cells in stomach * Gastric anti-parietal cell antibodies cause atrophy – loss of IF * Body unable to absorb vit B12 if there is no IF, resulting in macrocytic anaemia * Signs and symptoms: * Glossitis * Oral ulceration * Neuropsychiatric disturbance (mood, memory, cognition) * Peripheral neuropathy (paraesthesia)

Question 73

**Discuss the aetiology and pathophysiology of rheumatic fever**

Answer 73

Rheumatic fever: Disease of the developing world: autoimmune process following infection with group A streptococci * Jones criteria: carditis, arthritis, chorea, erythema marginatum & subcutaneous nodules * Chronic destruction of cardiac valves and resultant cardiac failure

Question 74

**Discuss the aetiology and pathophysiology of** **Sjögren syndrome​**

Answer 74

Sjögren syndrome: Lymphocytic infiltration of exocrine glands and subsequent destruction * Aetiology: * Genetic factors (HLA) * Environmental (EBV, hep C, human T cell leukaemia virus) * Hormonal (e.g. oestrogen)

Question 75

**Compare the key autoimmune mechanisms of pemphigus and pemphigoid (2 points)**

Answer 75

Pemphigus and pemphigoid (type 2 hypersensitivity “cytotoxic” reactions): * Pemphigus – antibodies against _desmoglein_ (desmoglein 1 and 3) * Pemphigoid – antibodies against _hemidesmosome_ (BPAG 1 and BPAG2)

Question 76

**Describe the pathogenesis of bullous pemphigoid (5 points)**

Answer 76

Bullous pemphigoid pathogenesis: 1. Fab (variable region) of IgG _auto-antibodies_ bind to _BPAG-1_ and _BPAG-2_ of _hemidesmosomes_ 2. Fc (constant region) of IgG then binds to complement protein C1 → initiates _complement cascade_ → C3a, C4a, and C5a (mast cell chemotactic factors) 3. Mast cells arrive and degranulate → TNF-​α, LKT, cytokines (WBC chemoactic factors) 4. WBCs (i.e. neutrophils, eosinophils, T cells, macrophages) arrive and release _proteolytic enzymes_ against BPAG-1 and BPAG-2 antigens of hemidesmosomes 5. Proteolysis occurs and bullous pemphigoid progresses: * _Subepidermal_ bullous (blister) beneath subepidermal cells of stratum basale * Negative Nikolsky sign (as desmosomes between cells of stratum spinosum remain unaffected and so retain integrity)

Question 77

**Describe the pathogenesis of pemphigus vulgaris (5 points)**

Answer 77

Pemphigus vulgaris pathogenesis: 1. Fab (variable region) of IgG _auto-antibodies_ bind to _desmoglein proteins_ of _desmosomes_ (epidermis = types 1 and 3; mucosa = only type 3) 2. Triggers _apoptosis_ which results in the release of _protease enzymes_ by the affected cells 3. Protease enzymes _breakdown desmogein proteins of desmosomes_, resulting in _acantholysis_ (cells detach from each other) 4. Since hemidesmosomes are not affected, the basal cells of the stratum basale remain anchored to the underlying basement membrane, but separate from the more superficial cells of the stratum spinosum → _tombstoning effect_ 5. _Intraepidermal_ bullae (blisters) form throughout: * Positive Nikolsky sign (as desmosomes between cells of stratum spinosum have undergone acantholysis) * Presence of Tzanck cells in areas of acantholysis

Question 78

**Recall the difference between mucocutaneous and mucosal pemphigus vulgaris**

Answer 78

Question 79

**Describe mucous membrane pemphigoid**

Answer 79

Mucous membrane pemphigoid (cicatricial pemphigoid): 1. Most significant complication is _eye involvement_ 2. Similar to pemphigus vulgaris, but not as severe, and _healing results in scar formation_ (hence 'cicatricial' pemphigoid) 3. Oral mucosal lesions in mucous membrane pemphigoid appear as vesicles or bullae that, unlike the lesions of pemphigus vulgaris, may be intact because the _epithelium is not as friable_ 4. Although epithelium is not as friable, there is still a _positive Nikolsky sign_ 5. Oral lesions _frequently limited to the gingiva_. 6. The gingival lesions have been called _desquamative gingivitis_ 7. The appearance _ranges from erythema to ulceration_ and _involves both the marginal and attached gingiva_

Question 80

**Recall the pathogenesis and clinical features of lichen planus**

Answer 80

Question 81

**Describe the autoimmune response in periodontal disease**

Answer 81

Periodontal disease – loss of the normal supporting tissues of the teeth and a humoral and cellular immune response to bacterial antigens of dental plaque which accumulates at the dentogingival junction. Observations of autoimmune response in periodontal disease: * Genetic predisposition (HLA) * Higher incidence of periodontal disease in patients with diabetes * Autoantibodies against ECM found in serum of patient with aggressive periodontitis * Autoimmune mechanisms prominent in aetiology of gingival lesions.

Question 82

**Define allergy, allergen and hapten**

Answer 82

Allergy – a chronic condition involving an abnormal reaction to an ordinarily harmless substance, i.e. allergen Allergen – a substance capable of inducing hypersensitivity or an allergic reaction, e.g. latex Hapten – a small molecule that elicits an immune response only when attached to a large carrier molecule (usually a protein). The carrier molecule does not elicit a response by itself.

Question 83

**Describe the type I hypersensitivity reaction and provide clinical examples**

Answer 83

Type I hypersensitivity (“anaphylactic”) reaction: * Antigen presented to CD4+ Th2 cells * B cells recruited and IgE antibodies formed * IgE binds to granular cells (e.g. mast cells and basophils) – sensitization * Re-exposure to the same antigen leads to release of mediators from granular cells – degradation * Mediators: histamine, leukotriene (LKT), platelet-activating factor (PAF), prostaglandin (PG) * Clinical examples: * Anaphylaxis * Urticaria * Allergic asthma * Drug allergy (e.g. penicillin) * Allergic rhinitis (i.e. hey fever)

Question 84

**Describe the type II hypersensitivity reaction and provide clinical examples**

Answer 84

Type II hypersensitivity (“cytotoxic”) reaction IgG or IgM antibody binds to cellular antigen, leading to activation of complement. IgG can also mediate antibody-dependant cell-mediated cytotoxicity. Complement dependant cytotoxicity: * Transfusion reaction – rapid destruction of the donor red blood cells by host antibodies * Autoimmune haemolytic anaemia * _Erythroblastosis fetalis_ * Goodpasture’s syndrome Antibody-dependant cell-mediated cytotoxicity: * Transplant rejection * Immune reaction against neoplasms * Immune reaction against parasites

Question 85

**Describe the type III hypersensitivity reaction and provide clinical examples**

Answer 85

Type III hypersensitivity (“immune complex”) reaction: Phase 1 – soluble immune complexes are formed by the combining of antigens and antibodies Phase 2 – Ab-Ag complexes deposit in small vessels where blood flow is reduced (e.g. joints, kidneys): * Inflammation * Complement binding * Platelet aggregation Examples: * _Systemic lupus erythematosus_ * Rheumatoid arthritis * Acute glomerulonephritis – commonly occurs after streptococcus infection * Farmer’s lung – inflammation of alveolar walls à increased collagen and decreased lung compliance

Question 86

**Describe the type IV hypersensitivity reaction and provide clinical examples**

Answer 86

Type IV hypersensitivity (“delayed”) reaction: * Cell-mediated response (T lymphocytes) * MHC II-antigen complex elicits macrophage response * Proliferation of T lymphocytes (T and B cells) * Inflammatory reaction * Reaction takes several days to develop (cell signalling, and protein synthesis takes time) Two main phases of type 4 hypersensitivity: 1. Sensitization: macrophage (Mφ) + CD4+ T lymphocyte → memory CD4+ T lymphocyte (MT) 2. Re-exposure: (Mφ) + MT → effector CD4+ Th1 cell (IL-2, IFN-γ) → leukocytes, CD8+, Mφ Examples: * Allergic contact dermatitis * Autoimmune myocarditis * Mantoux test

Question 87

**Describe the type V hypersensitivity reaction and provide clinical examples**

Answer 87

Type V hypersensitivity (“autoimmune”) reaction: * Autoimmune disease – antibodies bind to specific cell target receptors * Type V not classically used as part of the Gell and Coomb’s classification Examples: * _Graves’ diseases_ * Myasthenia gravis

Question 88

**Recall the Gell and Coombs classification of hypersentivity reactions (Type I–Type IV)**

Answer 88

Question 89

**Recall the mnemonic for the types of hypersensitivity and the respective antibody/cell**

Answer 89

Mnemonic and respective antibody/cell: Type I–Type IV * ACID: * **_A_**naphylaxis * **_C_**ytotoxic * **_I_**mmune complex * **_D_**elayed * EGG(T): * Ig**_E_** * Ig**_G_** * Ig**_G_** * _T_ lymphocyte

Question 90

**Define pathogenicity**

Answer 90

The _ability_ of an organism to _cause_ disease

Question 91

**Define virulence**

Answer 91

The _extent_ of pathology (harm) caused by the organism

Question 92

**Describe the regulation of bacterial virulence**

Answer 92

Two major regulatory control mechanisms to control expression of virulence genes (2 points): 1. Sigma factors: * Protein synthesis of bacterial RNA polymerases control initiation of transcription * Regulate prokaryotic gene expression in response to microenvironment. 2. Two component system: * Sensor protein embedded in bacterial membrane “senses” different physiological conditions of bacterial cell * Response regulator which binds to the promotor region of a gene to activate or repress transcription.

Question 93

**List 7 mechanisms which microbes employ to overcome host immunity**

Answer 93

Mechanisms which microbes employ to _overcome_ host immunity – i.e. _mechanisms of pathogenicity_: "**_C_**orona **_V_**irus **_V_**accine **_C_**ould **_E_**nrage **_R_**ebellious **_A_**ntivaxxers" 1. **_C_**hanging out protein expression 2. **_V_**iral antigenic drift and shift 3. **_V_**iral interference with antigen presentation 4. ​**_C_**ounteract complement 5. **_E_**xtra cell wall protection 6. **_R_**ender phagocytosis ineffective 7. **_A_**void phagocytosis

Question 94

**Mechanisms of pathogenicity**: * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe changing out protein expression**

Answer 94

Changing out protein expression (viruses): * Virus proteins may up-regulate host cell proteins that inhibit apoptosis * Ability of virus to mutate genotype (and hence phenotype by changing out protein expression) to escape host immune response Viruses are obligate intracellular parasites, and can manipulate the host cell in which it is residing to benefit its own survival.

Question 95

**Mechanisms of pathogenicity:** * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe viral antigenic drift**

Answer 95

Viral antigenic drift: * Evolutionary/variation mechanism by which viruses mutate the genetic code for antibody-binding site morphology * Creation of new virus, not effectively targeted by pre-existing antibodies * Influenza A, B and C- glycoproteins differ between flu subtypes (e.g., H1N1, H3N2, H5N1) * Seasonal variation of flu strains (and hence vaccination)

Question 96

**Mechanisms of pathogenicity:** * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe viral antigenic shift**

Answer 96

Viral antigenic shift: * The combination of ≥2 viral strains to form new virus with combination of both surface antigens * Occurs only in influenza A * Results in major reorganisation of strains * Responsible for jumping between species and pandemics One species passes viral strain to intermediate host animal, a human also passes on a separate strain to the same animal. Genes from both strains combine to form new strain which can jump from intermediate host to humans.

Question 97

**Mechanisms of pathogenicity:** * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe viral interference with antigen presentation**

Answer 97

Viral interference with antigen presentation: * Viruses can prevent proteasomal fragmentation (needed so fragment can be presented on MHC) * Block synthesis of MHC molecule itself * Redirection of endogenous MHC-antigen complexes to cytosol for destruction → MHC doesn't even make it to the cell surface of APC * Exclusion of APC presentation

Question 98

**Mechanisms of pathogenicity:** * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe how microbes counteract complement**

Answer 98

_Intracellular_ bacteria survive and replicate inside host cells. They enter host cells via receptors or phago-/endocytosis. Whilst intracellular they escape antibodies and avoid subsequent complement mechanisms of host immune system. Intracellular lifestyles of bacteria: * Facultative intracellular bacteria – capable of living either inside or outside of host cells: * Listeria monocytogenes, Salmonella typhi, legionella. * Obligatory intrasellar bacteria – only survive inside host cells as reliant on intracellular host resources: * Chlamydia, rickettsia, Coxiella, Mycobacterium tuberculosis. Viruses are by nature _obligate intracellular_ parasites and so naturally avoid the complement system once inside the host cell. Viruses can interfere with the host cell to prevent the host cell itself from activating complement (*viral interference with antigen presentation*)

Question 99

**Mechanisms of pathogenicity:** * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe the extra cell wall protection of microbes**

Answer 99

Extra cell wall protection: Two major groups of bacteria based on cell wall structure: * Gram-positive * Cell wall components: peptidoglycan and teichoic acid * Common microbes: *Staphylococcus aureus*, *Staphylococcus epidermidis*, streptococci * Gram-negative * Cell wall component: LPS/endotoxin * Primary receptor for endotoxin is CD14 (found on macrophages) * Common microbes: *E. coli*, *P. aeruginosa*, meningococci Bacterial capsule for extra cell wall protection: * Coat of polysaccharide (sugar) “slime” – glycocalyx (esp. Gram -ve) * External to cell membrane and cell wall * Protection against desiccation * Enhances ability to adhere to host * Protection from phagocytosis: * does not all allow opsonization by antibodies → frustrated phagocytosis * Virulence factor Notorious species: *Streptococcus pneumoniae*, *Neisseria meningitidis*, *Pseudomonas aeruginosa*

Question 100

**Mechanisms of pathogenicity:** * **Changing out protein expression** * **Viral antigenic drift and shift** * **Viral interference with antigen presentation** * **​Counteract complement** * **Extra cell wall protection** * **Render phagocytosis ineffective** * **Avoid phagocytosis** **Describe how microbes can avoid phagocytosis and employ mechanisms to render phagocytosis ineffective**

Answer 100

Avoid phagocytosis: * Intracellular lifestyle of bacteria and viruses – able to survive, replicate and avoid clearance by phagocytes in ECM Render phagocytosis ineffective: * Bacterial capsule prevents opsonization → “frustrated phagocytosis”

Question 101

**Describe how viruses can escape the host immune system by mutation mechanisms (pathogenicity) (6 points):**

Answer 101

Viral escape – mutation mechanisms (pathogenicity) (6 points): "**_E_**bola **_E_**pidemic **_S_**hould **_B_**e **_C_**arefully **_I_**dentified" 1. **_E_**vasion of NK cell immunity – encode decoy analogue of MHC molecules to veto the NK killing process 2. **_E_**vasion of antibody and complement – antigenic drift and antigenic shift 3. **_S_**equestration – infection of host cells to store genetic information – virus remains in latent state 4. **_B_**lockade of antigen presentation – disruption of MHC synthesis and APC presentation 5. **_C_**ytokine evasion – encode mimics of normal cytokines (virokines) which inhibit normal immune cells 6. **_I_**nhibition of apoptosis by viral proteins – up regulate proteins to inhibit apoptotic cellular events

Question 102

**Recall the differences between antigenic drift and antigenic shift**

Answer 102

Antigenic dift vs antigenic shift

Question 103

**Define primary (inherited) immunodeficiency (PID) and list 6 causes of PID**

Answer 103

Primary immunodeficiency disorder (PID) refers to a heterogeneous group of disorders characterized by poor or absent function in one or more components of the immune system. Causes of primary immunodeficiency (6 points): "**_P_**eter **_P_**an **_S_**hould **_C_**hallenge **_P_**irates **_C_**arefully" 1. “**_P_**ure” T cell disorders 2. “**_P_**ure” B cell disorders 3. **_S_**evere combined immunodeficiency (SCID) 4. **_C_**ombined immunodeficiencies 5. **_P_**hagocyte deficiencies 6. **_C_**omplement deficiencies

Question 104

**Describe "pure" T cell disorder in primary immunodeficiency**

Answer 104

“Pure” T cell disorders – affecting T cell arm of acquired immunity: * _Complete_ insufficiency of T cell function can result from hereditary conditions such as severe combined immunodeficiency (JAK3-deficient SCID: T-, B+): * JAK3 (Janus Kinase 3) deficiency is an autosomal recessive form of SCID. * It is characterized by _lack of circulating T and NK cells_ but normal number of B lymphocytes.

Question 105

**Describe "pure" B cell disorder in primary immunodeficiency**

Answer 105

“Pure” B cell disorder – most common type of primary immunodeficiency (~50% of PID cases) Heterogeneous group of disorders (\>20) characterised by increased susceptibility to respiratory tract infections with bacteria, particularly *Streptococcus pneumoniae* and *Haemophilus influenzae*. Clinical examples of “Pure” B cell disorders: * XLA (X-linked agammaglobuminaemia, or Bruton’s syndrome) * Inability to mature B cells * Complete or incomplete lack of antibodies. * Common variable immunodeficiency (ID): * Gene deletion of surface proteins and cytokine receptors * Lack of IgG, IgM, IgA. * Selective IgA deficiency: * Undetectable IgA * Most common genetic primary immunodeficiency (PID).

Question 106

**Explain severed combined immunodeficiency (SCID)**

Answer 106

SCID (more aggressive form of CID) is sometimes referred to as 'bubble boy disease': * 1 in 100,000 live births * Can be X-linked or autosomal recessive * Multiple variants of genetic mutations responsible * Early diagnosis imperative * Without treatment, fatal within first year * Treated with stem cell (BM) transplant, gene therapy, enzyme replacement therapy. * Bubble boy disease _Do not give live vaccines._ Hx and exam: recurrent infections, failure to thrive (poor weight gain), chronic diarrhoea; absence of lymphoid tissue, diffuse erythematous rash, microcephaly, skeletal abnormalities. Risk factors for SCID: FHx of infant death, FHx SCID (consanguinity).

Question 107

**Describe combined immunodeficiency (CID)**

Answer 107

Combined immunodeficiency (CID) Overview of combined immunodeficiency: * Categorized into presence/absence of T cells and B cells (T-/B+) or (T-/B-) * May also have normal T cell count * If associated with neurological findings, may be life-threatening Clinical presentation: * \< 12 months * Chronic diarrhoea * Failure to thrive * Severe, recurrent infections with opportunistic pathogens * Skin rashes Clinical examples: * _SCID (more aggressive form of CID)_ * _DiGeorge syndrome_ * _Wiskott-Aldrich syndrome_ * Ataxia-telangiectasia

Question 108

**Explain DiGeorge syndrome**

Answer 108

DiGeorge syndrome: * Deletion in _chromosome 22_ (segment 22q11.2) * Neurological, immunological, endocrinological, or cognitive defects * Treatment depends clinical manifestations present in the individual patients * Symptomatic management Hx and exam: cyanosis, heart failure, facial features (bulbous nose tip and prominent ears), cleft lip/palate, growth failure, seizure/tetany, learning disorder, frequent infection, hypocalcaemia, hypoplastic thalamus.

Question 109

**Explain Wiskott-Aldrich syndrome**

Answer 109

Wiskott-Aldrich syndrome: * X-linked condition characterised by _thrombocytopenia_ * Small platelet size is consistent feature * Eczema, recurrent infections and easy bruising * Autoimmunity complicates up to 70% of cases * Increased risk of haematological malignancies

Question 110

**Give 3 examples of phagocyte deficiency in PID**

Answer 110

Examples of phagocyte deficiency in PID: 1. Chronic granulomatous disease – severe infection, abscess, granuloma formation 2. Hyper IgE syndrome – chronic dermatitis, recurrent severe lung infection, bone fragility, failure to lose primary teeth 3. Leukocyte adhesion deficiency – recurrent severe bacterial infections, poor wound healing

Question 111

**Recall the complement deficiencies and their respective clinical manifestations in PID**

Answer 111

Specific complement deficiency results in specific clinical manifestations

Question 112

**Define secondary (acquired) immunodeficiency and list 6 example causes**

Answer 112

Secondary immunodeficiency is an _acquired_ state in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. It can result from various immunosuppressive processes/agents: 1. Malnutrition 2. Aging 3. Infectious disease 4. Malignant 5. Medications 6. Environmental toxins – mercury and other heavy metals, pesticides, and petrochemicals

Question 113

**Describe the aetiology and pathophysiology of human immunodeficiency virus (HIV)**

Answer 113

HIV aetiology and pathophysiology Aetiology: * Retrovirus – infects and replicates in CD4+ T cells and macrophages * Transmitted via blood, blood products, sexual fluids and breast milk * 0.1% per contact for heterosexual transmission (increases with concurrent ulcerative STDs, high HIV viral load and lack of ART) Pathophysiology: * HIV infection follows a 7-step mechanism: * Fusion, entry, reverse transcription, integration, synthesis, budding, maturation * Provirus resides in host cell nucleus and infected cells remain quiescent * Uses host cell to replicate itself * High level of viral replication within few weeks * Decline in CD4+ T cells * Progression to AIDS and death if not treated

Question 114

**List the 4 stages of HIV presentation**

Answer 114

HIV stages of presentation (4 points): 1. Acute seroconversion 2. Asymptomatic clinical latency 3. Symptomatic period (milder immune dysfunction) 4. Severe immunodeficiency and AIDS

Question 115

**Recall the mechanism of HIV infection (7 points)**

Answer 115

Mechanism of HIV infection (7 points): 1. _Fusion_ to host cell 2. _Entry_ of HIV contents: RNA, reverse transcriptase and integrase 3. _Reverse transcription_ of viral RNA to create viral DNA 4. _Integration_ of viral DNA into host DNA via integrase enzyme 5. _Synthesis_ of viral proteins by host using HIV RNA as genomic RNA 6. _Budding_ of immature HIV virions containing new RNA and proteins 7. _Maturation_ of virus by protease releasing individual HIV proteins

Question 116

**Describe the process and manifestation of HIV seroconversion**

Answer 116

Seroconversion is the period during which the specific HIV antibodies develop and become _detectable_ in the blood. Manifestation of HIV seroconversion:

Question 117

Define AIDS and list some examples of AIDS defining illnesses

Answer 117

Acquired immunodeficiency syndrome (AIDS) – CD4 count \<200 or AIDS defining illnesses: * Candidiasis of oesophagus * Candidiasis of upper airways * Cytomegalovirus * CMV retinitis * Encephalopathy * Multifocal leukoencephalopathy * Chronic herpes simplex * Kaposi’s sarcoma * Lymphoma * Mycobacterium tuberculosis * Cerebral toxoplasmosis * HIV wasting syndrome * Cervical cancer * Pneumocystis jirovecii pneumonia.

Question 118

**Describe HIV diagnosis and management**

Answer 118

HIV diagnosis: * _Fourth generation HIV test (ELISA)_ – tests for p24 antigen as well as antibodies, so are better suited for detecting recent infection (reduces risk of false negative result during 12-week window period) * High levels of p24 are present in the blood during the short period between HIV infection and seroconversion, before fading away * Test routinely used in the UK. HIV management (4 points): 1. Antiretroviral drugs 2. Counselling (pre- and post- testing) 3. Vaccinations 4. Micronutrient supplementation