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

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 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:

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 • 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.

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 • 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

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 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
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 - 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 )

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 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

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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) Pneumococcal conjugate vaccine

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
(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

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❖ 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
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 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

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115

116

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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

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❖ 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

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❖ 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

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❖ 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

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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) →

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 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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