2. Immunology arranged [Medical Books VN PDF

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LYMPHOID STRUCTURES 96 Mention the action of outer cortex in lymph nodes → contain number if CD4 T-cels within the interfollicular regions to allow for T-B interaction Mention the action of paracortical zone in lymph nodes → lies internal to the cortex, contain T-lymphocytes ad dendritic cells Mentio the action of medulla in lymph nodes : it consists of medullary cords contain B-cells, plasma cells and macrophages. Medullary sinuses which contain reticular cells and macrophages Mention the action of cortex in lymph nodes → it form the lymphoid follicles either primary follicles (dense, dormant), secondary (with pale germinal centers) they contain B-cells 97 Describe the lymphatic drainage of the LL: - Lateral foot & dorsal leg → drain to popliteal lymph nodes → inguinal LNs - Medial foot, leg and thigh → drain to inguinal lymph nodes Describe the lymphatic system composition: • Superficial lymphatic vessels → follow the venous system, drain skin & SC tissue • Deep lymphatic vessels → follow the arterial system, drain deep muscles & superficial lymphatic vessels 98 Normal action of spleen in immune response: • > 50% of body total Igs produced by splenic B-lymphocytes, among them splenic opsonizing antibodies → clearance of capsulated bacteria (spleen responsile for activation of complement not production of complement)

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CELLULAR COMPONENTS 99

Signaling pathway of NF-κB: • Normally NF-kB present as inactivated protein, bound to I-κB inhibitory protein. • Attachment of inflammatory mediators to the cells as TLR, bacterial products … lead to activation of IκB kinase which lead toubiquitation of the protein & hence destry inhibitory protein I-κB → release of free NF-κB • NF-κB act as transcription factor→ rlease of many inflammatory mediator (but usually self-limited, as NF-κB lead to ↑↑ production of I-κB)

Crohn’s disease Usually affect terminal ileum region → cause defective in reabsorption in bile 2

acid → ↓absorption of fat soluble vitamins → Vitamin K deficiency (bleeding tendency) o NOD2 mutation is implicated in pathogenesis of CD. o Normally, NOD2 “intra-cellular microbial receptor” produces a cascade → activation of NF-κB cytokine production & help innate immunity. o Mutations in NOD2 in CD ↓↓ activation of NF-κB → ↓↓ cytokine production & innate immunity → allow intestinal microbes to invade the mucosa → exaggerated response → chronic inflammation. 100 101 Describe the process of T-lymphocyte maturation: • It occur during first trimester in the thymus • Pro T-cells → double negative cells, reach the thymus (in the subcapsular zone) • TCR gene rearrangement begin by rearrangement of β chain → situation of both CD4, CD8 antigens → immature T-cells which are double positive (cortex) • Then, rearrangement of α chain → positive selection (which occur in cortex, failed cells after interaction of thymic cortical epithelium undergo apoptosis)& negative selection (occur in the medulla, failed cells after interaction with medullary epithelial cells & dendritic cells undergo apoptosis ) • Once positive selection is completed, loss of one the CD4 or CD8 receptors to be mature T-ccells

Immunological response in Leprosy: 3

• Tuberculoid : - Strong Th1 immunity → ↑↑ IL-2, IL-12, IFN-γ → activate macrophage → kill bacteria → damage skin due to inflammation • Lepromatous : - Strong Th2 – ↑↑ IL-4, IL-5, IL-10 → no macrophage activation → high bacterial load, negative lepromin test 102

Granuloma formation : • Either casseating (associated with infectious process), non casseating (non infectious) • Granulomatous diseases seen in minority of cases of Crohn’s diseases, but if exist→ highly suggestive of CD

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103 Mention sequence of events that occur after B-cells encounter an antigen for the first time: • Some of the activated B-cells in the lymphoid organs and peripheral tissues differentiate into short lived plasma cells that release IgM through T-cell independent B-cell activation • Majority of B-cells migrate to lymph nodes to form germinal centers → small amount of them changed to memory cells which is kept dormant in lymph nodes until next immune action. • Majority of B-cells transform in the lymph nodes into antibody secreting plasma cells • In germinal centers, isotype switching also occurs → but this need interaction of CD40 receptro on B-cells with CD40L on activated Th cells • Somatic hypermutation also occur in the germinal center which determine the affinity maturation of the antigen

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IMMUNE RESPONSES 104 105 Describe the secretion process of IgA & the source of secretory component

• after stimulation of the peyer patches → differentiate into plasma cells → synthetize the IgA dimers linked by J-chain (serum IgA is monomer) • IgA bind to polymeric Ig receptor (PIgR) found on the basolateral surface of the intestinal epithelium cells → transcytosis Mention bacteria contain IgA proteases, its role. • Neisseria, strept pneumoniae, Hemophilus • They inactivate IgA (by cleavage of the J-peptide) facilitate bacterial adherence to mucosa Describe the mechanism of IgE mediated mast ell degranulation. 7

• IgE is normally bound to high affinity IgE receptors on mast cells & basophils • When the antigen bind to the specific IgE → cross linking of the IgE antibodies → aggregation of the receptors on mast cells → ↑↑ activation of non receptor tyrosine kinase → degranulation 106 Other actions of C3a, C5a other than anaphylaxis: • C3a → recruit and activate neutrophils, monocytes, eosinophils, basophils • C5a → only eosinophils, basophils How C3b clear the immune complexes form blood: immune complexes formed by type III hypersensitivity reaction bind to CR1 receptors on RBCs → cleared in spleen & liver Importance of C3 in immune system: all 3 complement pathway converge to activate C3 into C3a (recruit phagocytic cells), C3b (opsonin, activate C5 → MAC) Where the complement bind to the IgG & IgM : they bind to the Ig at a region PROXIMAL to the Fc portion Describe the process of inititation the classical pathway of complement activation: - IgM / IgG are the ones responsible for activation of classical pathway of complement - C1 must bind the Fc portions of two different antibodies at specific C1 binding sites, so IgM activation (travel in pentamer) is more easier than activation IgG - IgM activation before antigen recognition is disabled as the complement binding sites are hidden in the pentamer, before re-appear by conformational changes. - The complement binding sites on Ig is different from Fc receptor binding site, complement attach to proximal part of the Fc close to the hinge joint Overview about opsonisation:

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Describe the steps of ubiquitin proteasome pathway (UPP): • Ubiquitin is an intra-cellular protein that tag the protein & mark them for destruction by the help of ubiquitin ligase (which recognize the protein) • These tagged proteins taken up by proteasomes to be degraded into its amino acids → so that can be effectively coupled with MHC-I by TAP complex Describe the mechanism of opsonisation: • The antigen bind to the IgG to its Fab fragment, while the IgG itself bind to the macrophage by its Fc portion this binding stimulate the act of phagocytosis. Other opsonins : (+) mannose binding lectin, CRP 107 Angioedema :

o ACE inhibitors : can occur even years after the treatment beginning o C1 esterase inhibitor 1) Inhibition of C1 mediated excess activation of C2, C4 9

2) Inhibit Kallikerin → ↓↓ kininogen → bradykinin • C1 inhibitor deficiency : • Occur in childhood, early adolescent • ↑↑ excess activation of C2, C4 (no clinical picture) • ↑↑ bradykinin (VD) 1) Facial swelling without urticarial 2) Life threatening laryngeal edema 3) GIT manifestations • Treatment : C1INH concentrate, kallikerin inhibitor 108

Mention the inflammatory & anti-inflammatory cytokines produced by different T cells - IL-10 → ↓↓ cellular immunity with favoring in ↑↑ activation of the humoral immunity - When the APCs is macrophage → it produce IL-12 to activate Th1 → IFN-γ 10

- Other APCs → produce IL-4 → ↑↑ Th2

What are functions of type I & II interferons: • Type I interferons (interferon α, β): Synthetized by human cells in response to viral infection They bind to receptors (apocrine / paracrine signaling) → ↑↑ enzymes to stop protein synthesis as RHase L (endonuclease → ↓↓ all RNA) and protein kinase R (↓↓ eIF-2 → ↓↓ translation) These enzymes active only in presence of ds RNA (in viral replication ) 11

so these changes only act specifically on viral infected cells ↑↑ MHC-I → ↑↑ NK cell & Tc cells • Type II interferon (interferon γ): Produced by Th1, NK cells ↑↑ Th1, MHC-II …. Immunological role Mechanism of cachexia by TNF-α : - Influence on hypothalamus → ↓↓ appetite - ↑↑ BMR - Also TNF-α → ↑↑ acute ohase reactant , not only by IL-6

Actions of IL-8: it is produced from the macrophage triggering neutrophils to enter the site of infection, induce phagocytosis in neutrophils 109

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110 What is the significance of CD 21: • Pre-B lymphocytes show CD19, CD20 …… but mature circulating B-cells show CD19, CD20, CD21 111 Why are polysaccharide vaccine only can be given to infancy. Due to immature huoral immune system < 2 years, the vaccination given must be conjugated with tetanus toxoid to enhance T-cell activation 7 production of memory cells.

Mention the difference between pneumococcal polysaccharide & conjugate vaccine. Polysaccharide vaccine (PPSV23) Contain more strains of bacteria (23) Antibody levels decline over 5 years Not immunogenic in children < 2 years Used for all adults > 65 years. Used for 2 – 64 years with chronic illness (they need its wide spectrum) 112

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Pneumococcal conjugate vaccine (PCV13) Less strains, narrower index Higher & long lasting immune response (due to memory cells) Strongly immunogenic in infancy Part of routine children vaccination Used for all adults > 65 years

What are the substance released from mast cells & basophils during type I reaction: Histamine & tryptase (which is specific for mast cells, ↑↑ levels support anaphylaxis diagnosis)

113 Histological finding in serum sickness: • Small vessel vasculitis with fibrinoid necrosis • Intense neutrophil infiltration • Deposition of IgG / IgM fixed with complement → hypo-complementemia (↓↓C3) Causes of serum sickness: 1) Chimeric monocloncal antibodies (-ximab) 2) Non-human immunoglobulin (e.g. venom antitoxins) 3) Non protein drugs e.g. (penicillin, cefaclor, TMP-SMX) Describe in detailed the pathogenesis of type IV hypersensitivity reaction: • Sensitization phase: (10 – 14 day) cutaneous dendritic cells (APCs) take 14

up the hapten, express them on MHC- I / II as hapten conjugated peptides → LN to interact with CD4 & CD8 T cells → activation & clonal expansion • Elicitation phase: (2 – 3 days) rexposure to the same antigen (or after first exposure of highly antigenic antigen) → hapten is taken up by the cells → activation of sensitized T cells → inflammatory response

Systemic mastocytosis : • Clonal mast cell proliferation in BM, skin , … etc. • Mutation of KIT (tyrosine kinase, CD 117) → ↑↑ expression of mast cell tryptase • ↑↑ mast cells → ↑↑ histamine release from de-granulation → symptoms suggestive of histamine excess. (from the symptoms of excess hisamine is ↑↑ gastric secretions & acidity) 114 Cause of anaphylactic reactions in patients with IgA deficiency Patients with severe IgA deficiency → can form IgE antibodies against IgA. Wen blood is transfused; it contains small amounts of IgA → bind to anti-IgA → anaphylaxis. So these patients should wear medical bracelet to receive blood washed from IgA Mechanism of acute hemolytic transfusion reaction: - Due to ABO incompatibility between the donor & recipient blood - The recipient antibodies IgM + donor RBCs → complement activation ↑↑ C3a, C5a → anaphylaxis, shock Membrane attack complex → complement mediated cell lysis 15

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Lab changes in DiGeorge syndrome : ↓↓ T-cells (due to thymus aplasia), normal levels of B-cells & Igs IL-12 receptor deficiency (IFN-γ receptor): • Treatment of IL-12 receptor deficiency (IFN-γ receptor): lifelong treatment of continuous anti-TB antibiotics (suspect in early disseminated TB) • Describe the mechanism of action of IFN-γ in TB: Normally, TB bacteria → ↑↑ IL-12 → stimulate T-cells, NK cells → IFN-γ → dind to receptor activate Janus kinase 1 & 2 → signaling via STAT1 (JAK-STAT pathway) → activation.

Immunological response of TB: • After failure of the macrophage to kill the TB, it present its antigen on MHC-II and release of IL-12 → differentiation of Th (CD4 cells) into Th1 • Th1 → ↑↑ IFN-γ ↑↑ ability of the macrophages to kill the bacteria, formation of granuloma that wall off the mycobacteria to make the center of the granulomas acidic & hypoxic • N.B.: after intial exposure, BCG is always negative, as it take around 8 weeks to be positive results 17

Why in IL-12 receptor deficiency, IFN-γ ↓↓, what is the relation. • Whe antigens are presented by macrophage → ↑↑ IL-12 to help differentiation of T-cells to Th1 → which produce IFN-γ • Th1 response is the mainstream for TB, so here dissiminated TB will occur 117 SCID: • Clinical picture of SCID: recurrent infections by viruses, bacteria, fungi, opportunistic infections, chronic diarrhea, FTT • Diagnosis & DD of SCID: - Screening for SCID in US is done after birth (measure IGs, lymphocytes) - DD must include congenital HIV infection

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Why adenosine deaminase deficiency cause SCID, treatment : • ADA deaminate the adenosine to inosine to eliminate adenosine from cells, as ↑↑ adenosine accumulation is toxic to lymphocytes • This specific deficiency can be treated by retroviral gene therapy is promising

Immunological disorder in Wiskott Aldrich syndrome: it is combined B, T lymphocytic disorder, recurrent infetions occur by capulated organisms and opportunistic pathogens, infection worth as the patient age due to ↓↓ maternal IgG, treatment is BM transplantation

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Mention the cascade of leucocyte migration & different types of LAD: • Rolling: due to attachment of neutrophils (Sialyl Lewis X or PSGL-1)to endothelium (E/P selectin) or neutrophilic L-selectin • PECAM-1 → they found primarily at the peripheral intercellular junctions of endothelial cells. • LAD1 (due to ↓↓ β2 integrin of Mac-1 & LFA1 = CD18) and LAD3 (↓↓ activation) → cause severe form of LAD without pus formation, delayed separation of the cord, poor wound healing • LAD2 → mild with no separation of the cord, less severe infections

Clinical picture of Chediak- Higashi syndrome : • Immunodeficiency: defective phagosome-lysosome fusion → abnormal giant lysosomal inclusions, recurrent infection by staph., strept. • Albinism: parital, due to abnormal melanin storage in melanocytes • Neurological symptoms : nystagmus, neuropathy, progressive neurodegeneration 20

What is the target of NBT & DHR tests in diagnosis of CGD. • They meaure the neutrophil superoxide production. • NHT → failure of the neutrophils to turn blue on adding NHT = CGD

118 119 Clinical picture of GVHD: - The immune phenomena is mediated by T-cells not –cells - Skin (earliest findings) diffuse maculopapular rash, more on palm & sole +/- desquamate in severe cases - GIT diarrhea, intestinal bleeding & abdominal pain - Liver abnormal elevated LFTs 21

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IMMUNOSUPPRESSANTS 120 describe the signal transduction of mTOR pathway: - when a growth factor bind to its receptor tyrosine kinase → autophosphyrylation → ↑↑ phosphoinsositide 3 kinse (PI3K) → [PIP2 → PIP3] - This lead to activation of protein kinase B (AKt) “serine therionine protein kinase” → activation of mTOR → induce angiogenesis, cell survival - mTOR inhibited by PTEN (phosphate and tensin homolog) → remove phosphate from PIP3 121

Mechanism of action of aldeslukin - It is Il-2 agonist which have the following effects: 1) T-cells → ↑↑ IL-2 → ↑↑ IL-2R IL-2/IL-2R interaction → ↑↑ action of CD4, CD8 2) Growth of B-cells 3) Activation of NK cells → it is the main mechanism behind its use for anticancer 122 Mechanism of EGFR and its role in cencer and cancer therapy: • EGFR is stimulated → downstream activation of KRAS → GTPase → stimulate cellular growth and proliferation • Many cancers (as colorectal, pancreas) → overexpress EGFR, activating mutation of KRASoncogene • Monoclonal antibodies agaisne EGFR (cetuximab, panitumumab) → 23

block EGFR → ↓↓ KRAS → ↓↓ cellular growth • These drugs act only in normal (wild type) KRAS tumors, so genetic testing is a must prior to administration of these drugs is essential to check either the KRASis normal or mutated as in mutated KRAS the drug will not act as the downstream activation of cell growth is still intact • Panitumumab → anti EGFR monocloncal antibody (as

cetuximab) Mechanism of action of Alemtuzumab → ind to CD52 → stimulate direct cytotoxic effect through complement fixation, ADCC Her-2/ neu positive associated with highly aggressive tumor, in contrast ER/PR positive has better outcome What is the role of Her/neu receptros • Trastzumab is mab against Her2 receptors → prevent activation of tyrosine kinase • Her2 oncogene is a part of epidermal gorwith factor receptor (C-erb2) with tyrosine kinase activity in the intracellular domain. • Tumors with ↑↑ HER2 → ↑↑ proliferation and resistance to apoptosis, with worse prognosis Mention the role of PD-1 in cancer immunotherapy: - Programmed death receptor 1 (PD-1) expressed on the surface of activated T-cells, when bound to its ligand (PD-L1) it ↓↓ Tc function → ↓↓ immunity - Many cancers ↑↑ PD-L1 - B7 → react with CD 28 activate T cells, while bind to CTLA-4 to inhibit them - Drugs against PD-1 used in melanoma and lung cancer; examples : nevolumab, pembrolizumab Describe the signaling pathway of melaonoma and role of vemarfunib : - V600E mutation of the BRAF (protein kinase) lead to more activation of the signaling → ↑↑ melanocyte proliferation

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