Fungi, bacteria, virus and parasites (p. 1)

A pathogen is a microorganism that is able to overcome the innate immune defenses (p. 50) 

A cytokine is any secreted protein that affects the behavior of of nearby cells with the appropriate receptor

Cytokines cause inflammation

p. 10

A chemokine is any secreted protein that attracts cells with an appropriate receptor

Chemokines cause inflammation

p. 10

Dendritic cell (most important antigen-presenting cell-type): Macropinocytosis or phagocytosis of pathogen -> degradation of pathogen -> peptide binds to MHC I molecules which are presented on cell surface -> recognition and activation of T cell (with co-stimulatory signals)

Macrophage: Phagocytise pathogen -> degradation of pathogen -> 

B lymphocyte:

Plasma cells arise from B cells when they encounter the antigen matching their B cell receptor. Some plasma cells reside in the peripheral lymp organs but most of them migrate to the bone marrow. Effector cells generated in MALT stay.

p. 26

Humoral immune response: Antibody-mediated immune response. Generated by plasma cells.

Cell-mediated immune response: The effect of effector T cells on pathogens. The most direct effect is that of cytotoxic T cells

p. 28 and 31

Neutralizing antibodies: Binds to foreing material (eg. bacterial toxin) to neutralise it. Eventually bound by Ig specific receptors on the surface of macrophages and internalised.

Opsonizing antibodies: Bind to bacteria (some evade binding by PRR on macrophages). Eventually bound by Ig specific receptors on the surface of macrophages and internalised.

Complement activating antibodies: Bind to bacteria and act as a receptor for the first protein of the complement system (C1)??

p. 29-30 and 65 (?)

MHC I is expressed by all cells. They present intercellularly produced peptides (eg. viral protein) and are recognised by CD8 cytotoxic T cells.

MHC II is expressed on antigen-presenting cells. They present phagocytised pathogen-derived peptide (eg. bacterial) and are recognised by CD4 TH1 and TH2 T cells.

p. 32-34

An immunogen can elicit an immune response, whereas an antigen can bind to an antibody. A protein for example is an antigen (can bind to antibidies) but cannot elicit an immune response by itself. Therefore, you have to inject adjuvant together with the protein in order to provoke an immune response.

Appendix I, p. 735

- Tight junctions between the epithelial cells

- Antimicrobial peptides (skin, gut, lungs)

- Cilial movement (lungs, nose)

- Mucus (Lungs, nose)

- IgA (lungs, nose)

- Enzymes (eyes (tears), gut)

- Low pH (gut)

- Fatty acids (skin)

- Competition with commensal bacteria

p. 46-47, fig. 2.7

Name the 3 phases of the immune response and their approximate duration.

What is the difference between the two first?

1- Innate immunity: 0-4 h

2- Early induced innate response: 4-96 h

3- Adaptive immune response: >96 h

p. 39

Innate immunity is facilitated by the cells present at the site of infection. After about 6 hours, neutrophils enter the tissue and later also monocytes (induced innate response)

Acidification

ROS

NO

Antimicrobial peptides

Enzymes

Competitors

p. 49, fig. 2.9

Pus is acculmulation of dead neutrophils after their single round of phagocytosis

p. 49

A white blood cell

p. 5

Macrophages: Are derived when monocytes entering infected tissue are exposed to M-CSF (macrophage colony-stimulating factor)

Dendritic cells: Are derived when monocytes entering th infected tissue are exposed to IL-4 and GM-CSF (granulocyte-macrophage colony-stimulating factor)

p. 51

Release of IL-1beta, IL-8 and TNFalpha (endogenous pyrogens) or the presence of LPS leads to production of prostaglandin E2 which affects the temperature center in hypothalamus to rise the body's temperature by burning brown fat and withdrawing blood from the surface.

chap. 2

The classical pathway: C1q in complex with C1r and C1s binds to PAMPs on a pathogen's surface. Upon binding, C1r cleaves C1s, which becomes activated. C4 is cleaved by C1s to C4a and C4b. The latter binds covalently to the pathogen surface. C2 binds to C4b and is cleaved by C1s to C2a and C2b. C2a binds C4b creating C4bC2a = C3 convertase. C3b opsonises the pathogen surface by binding with thioesterbond. C3b can bind C3 convertase to create C5 convertase, cleaving C5 to C5a and C5b.

The lectin pathway: Mannose-binding lectin (MBL) is an analog of C1q, and the protein MASP-2 to C1r/C1s. The pathway is the same as the classical.

The alternative pathway: Spontaneous hydrlysis of C3 in plasma leads to binding of factor B to C3(H2O). Factor B is then cleaved by factor D and C3(H2O)Bb = C3 convertase. C3 in plasma can be cleaved to C3a and C3b. The latter with the free thioester, which can bind a pathogen or will quickly be inactivated by reaction with H2O.

The membrane-attack complex: C5b bound to the pathogen surface binds C6 and then C7. A conformational change in C7 reveals a hydrophobic site that is then inserted into the membrane. C8, which also has a hydrophobic site, binds and forms the basis of 10 to 16 C9 molecules which form a pore in the membrane.

Amplification: C3b bound to the pathogen surface can bind factor B and thereby amplify the classical and lectin pathways.

C3a, C4a and C5a are inflammatory mediators: They are anaphylatoxins, because they can cause anaphylactic shock. C3a and C5a can activate mast cells. C5a increase expression adhesion molecules on circulating neutrophils and monocytes and increase their CR1 expression fig. 2.39

Chap. 2

-Liver: Acute-phase response => opsonisation, complement activation

-Hypothalamus: Fever (through Prostaglandin E2) => decreased viral and bacterial replication , increased antigen processing and specific immune response

-Bone marrow epithelium: Neutrophil release => Phagocytosis

-Fat, muscle: Energy mobilisation to increase body temperature

-Lymph nodes: TNF/alpha stimulates dendritic cells to migrate to lymph nodes and maturate ...initiation of adaptive immune response

chap. 2

CXCL-8 (IL-8) in blood vessel leads to activation of LFA-1 and CR3 (integrins) on neutrophils/monocytes => leukocyte arrest.

After extravasation, a gradient of CXCL-8 (IL-8) and CCL2 bound to proteoglycanc in the ECM guides the leukocytes to the site of infection

Chap. 2

Almost any cell experiencing a viral infection will start producing IFN-alpha and -beta, because dsRNA bound by TLR-4 leads to NF-kappa B and then IFN expression. They are secreted and act on receptors on same and neighboring cells. By Jak-Stat pathway gene expression of proteins is initiated. The effect of these proteins is to degrade dsRNA, block translation and viral replication.

Additionally, IFNalpha/beta cause upregulation of MHC I on all cells, expression of co-stimulatory molecules on macrophages and dendritic cells and activate NK cells 

chap. 2

1- A leukocyte in the blood vessel rolls along the activated endothelium due to weak binding of P-selectin and hours later E-selectin on the endothelium to glucoproteins on the leukocyte.

2- Binding of CXCL-8 (IL-8) to its receptor on the leukocyte activates the integrins LFA-1 and CR3, which can then binde to ICAMs on the endothelium => leukocyte arrest

3- LFA-1 and CR3 as well as PECAM on both leukocyte and in the intercellular space facilitate the extravasation.

4- Enzymes break down the basement membrane

5- Chemokine gradient of CXCL-8 (IL-8) and CCL2 lead the way to the site of infection

Chap. 2

Positive regulation: When factor B binds C3b on the pathogen surface and is cleaved to Bb resulting in C3bBb (C3 convertase) factor P binds to stabilise the complex.

Negative regulation: If C3b binds to host cells, menbrane-bound proteins compete for factor B binding or displaces Bb (DAF, factor H). Plasma proteins, factor I, cleaves C3b to iC3b when it is bound to host cells.

Chap. 2

Acute-phase proteins are secreted by hepatocytes upon IL-1, IL-6 and TNF-alpha. They are antibody-like structures that bind PAMPs and target the pathogens for phagocytosis.

-C-reactive protein: Binds phosphocholines

-Mannose-binding lectin: Binds mannoses and activates the complement system

- Pulmonary surfactant proteins: Binds pathogens in mucus

-among others

Chap. 2

Natural Killer cells have invariant receptors recognising components of the surface of an infected host cell

It is activated by IFN-alpha/beta or IL-12. If both IL-12 and TNF-alpha is present, the NK cell will secrete IFN-gamma => guide CD4 T-cell development towards TH1 cells (macrophage activation)

Binding of antibody to receptor causes antibody-dependent cellular cytotoxicity (ADCC)

2 receptor types: 1 recog. MHC I (negative signal) and 1 recog. activating ligand (positive signal) => the sum desides the outcome. KIR and KLR

p. 97

NKG2D is a receptor on NK cells, macrophage and CD8 cytotoxic T-cells. NKG2D ligand is expressed by infected, stressed or tumorigenic cells

p. 100

Innate-like lymphocytes:

- specific location in the body

- few gene rearrangements (RAG-1 and RAG-2)

- self-renewing in tissue

gamma:delta T-cells: in epithelia. Recognise molecules derived from infected cells (instead of the pathogen itself as alpha:beta T-cells)

B-1 cells: Expression of CD5. Located in the peritoneal and pleural cavities. Recognises polysaccharides and produce IgM without T-cell activation. Induce no immunological memory.

NK T-cells: Thymus and peripheral lymphoid organs. Rapid secretion of IL-4, IL-10 and IFN-gamma => regulatory function.

Natural antibody: IgM. Circulate the body, have weak affinity for pathogenic characteristics. Can even bind to self.

Chap. 2

IgG

Chap. 3

A hapten is a small protein that can act as carrier in immunisations when the organic molecule of interest does not elicit an immune response by itself

p. 736

T-cell receptor:

- 1 binding site

- never secreted

- alpha and beta chain (or gamma:delta)

- recognises MHC molecule + bound peptide

B-cell receptor:

- 2 identical binding sites

- secreted as antibodies

- light and heavy chain

- recognises antigen

Chap. 3

MHC I:

- 3 alpha and 1 beta domain

- 1 transmembrane segment

- expressed by all cells

- recognised by CD8 T-cells

MHC II:

- 2 alpha and 2 beta domains

- 2 transmembrane segments

- expressed by B-cells, macrophages and dendritic cells

- recognised by CD4 T-cells

Chap. 3

Light chain: V-J segments are joined.

Heavy chain: First, D-J segments are joined, then, V-DJ segments.

Recombination is facilitated by RAG-1 and RAG-2 with DNA repair proteins. Recombination signal sequences (RSSs) are flanking each segment: heptamer - 12/23 spacer - nonamer. When 2 segments are recombined it leads to either looping out of signal joint or inversion of a part of the DNA.

1- RAG-1 and -2 bind RSSs and join them

2- RAGs cleave the strands between RSS and segments and create hairpin ends on each strand

3- Coding joint: Ku stabilises the ends, recruits DNA-PK and artemis (nuclease that nicks DNA at unspecific site = p-nucleotides); TdT adds up to 20 nucleotides = n-nucleotides; DNA ligase IV ligate the strands together.

3- Signal joint: Ku stabilises the ends and DNA ligase IV ligates the ends together.

Chap. 4

1- many copies of each gene segment

2- junctional diversity due to recombination process

3- each heavy chain is combines with several light chains due to later recombination of light chain genes

4- somatic hypermutation

chap. 4

The entire T-cell receptor delta locus is located within the TCRalpha locus. Therefore, if a cell commit itself to alpha:beta T-cell, the delta locus is looped out by recombination

Chap. 4

IgM: pentamer

IgA: monomer (plasma) and dimer (mucus)

Each antibody contain an extra 18 aminiacids (with cysteine to make disulfide bond) and a peptide, J chain, joins the antibodies together

Chap. 4

disulfide bonds

location and number of oligosaccharides

number of C-domains

length of hinge region

p. 162

Which antibody class(s) can activate the classical complement pathway?

Which can activate the alternative?

Which can transfer across the placenta?

Which binds to Fc receptors of phagocytes?

Which binds to Fc receptors of mast cells, eosinophils and basophils?

classical pathway: IgG1, IgG3 and IgM

alternative pathway: IgA

placental transfer: IgGs

Fc receptor - phagocytes: IgGs, IgA, IgE (late ones)

Fc receptor - mast cells etc.: IgE

Fig. 4.16

Two polyA sites are present on the pre-mRNA, alternative splicing leads to either first one, secreted form, or last one, includes transmembrane segment.

Chap. 4

Activated B-cells express the enzyme Activation-Induced Cytidine Deaminase (AID) which alters C -> U in the V gene segment. This is repaired by DNA repair proteins => mutations

Chap. 4

After Activation-Induced Cytidine Deaminase (AID) has deaminased the cytindine in V segments of B-cell receptors DNA repair proteins take the resulting uracil away => ss nick.

Homologous recombination with pseudo V genes => altered gene sequence

Chap. 4

MHC I: Proteins from cytosolic bacteria or viruses. Upon IFN-stimulation the cell express LMP-2 and 7 which are components of the immunoproteasome. This complex degrades cytosolic proteins to peptides which are translocated to the ER by the transportercomplex TAP-1 and -2. On the inside of the ER membrane the MHC I alpha chain binds the chaperone calnexin and after binding to the beta chain, the complex binds MHC I loading complex (incl. TAP) to help load the peptide to the peptide-binding groove. After binding, the MHC I:peptide is transported to the cell surface. Self-peptides are also bound and presented.

Cross-presentation: If intravesicular or membrane-bound proteins are translocated to the cytosol they may be degraded by the immunoproteasome and in the end presented by MHC I.

MHC II: Protein from vesicular pathogen. In the endolysosomes pathogens are degraded by lysosomal proteins to peptides. When the vesicle fuses whit a MHC II-containing vesicle the pathgen-derived peptides load onto MHC II and are transported to the cell surface. In ER, MHC II binds transmembrane invariant chain (Ii) which prevent it from binding self-peptide and targets it for the acidic compartment. Ii is cleaved by cathepsin S to CLIP, which in the end dissociates. In vesicles, MHC II is stabilised by HLA-DM, a MHC II-like molecule that loads the peptide.

Cross-presentation: Autophagy translocates cytosolic proteins to vesicular compartment.

Chap. 5

MHC locus = HLA locus. Located on chromosome 6

MHC I: alpha chain genes: HLA-A, -B, -C. beta chain genes: on chromosome 15.

MHC II: alpha and beta chain genes are located next to each other: HLA- DP, -DR, -DQ

TAP-1 and -2 genes

LMP-2 and -7 genes

MHC I, TAP and LMP genes are IFN alpha/beta/gamma-induceable.

Locus is polygenic and highly polymorphic => diversity (increased by combination of alpha and beta chains)

In the locus: genes for TNF-alpha, -beta, complement

Chap. 5

Alloreactivity: Reaction of an individuals T-cells towards MHC II from another individual (transplant)

MHC restriction: TCR recognises not only the peptide but also the MHC molecule

Fig. 5.20 and 5.21

Superantigens are bacterial or viral products that bind both TCR and MHC II to activate the T-cell to produce cytokines that suppress the adaptive immune response and cause systemic toxicity

p. 207

CD1 is similar to MHC I in structure and MHC II in function. It binds bacterial gycolipids from the endocytic pathway. The T-cell activated by this presentation is neither CD4 nor CD8 positive!

P. 211

Many viruses produce immunoevasins which are proteins that block the presentation of viral proteins on the cell surface. Any step of the presentation process can be blocked.

Chap. 5

BCR: membrane-bound antibody + Ig-alpha and -beta (signaling function, ITAM, and localisation to membrane). ITAMs are phosphorylated by Lck and Fyn (Src-kinases). Phosphorylationsites docks SH2-domain proteins, Syk => signal

B-cell co-receptor: complex of CD19:CD21:CD81, CD21 is complement receptor CR2 -> binds complement bound to pathogen => phos. of CD19 by Src-kinases => stronger signal Fig. 6.25

More epitopes on pathogen surface => more dimerisation => stronger signal. Fig. 6.11

TCR: TCR + CD3 (gamma, delta, epsilon) + Zeta chain homodimer, ITAMs on CD3 (one each) and on Zeta chain (3x2). CD3 stabilises and targets receptor to membrane. Fig. 6.10. Lck and Fyn phosphorylates ITAMs => TCR associates with co-receptor (CD4/CD8) which stabilises the MHC:TCR binding. ZAP-70 binds with SH2-domains to phosphorylated ITAM and gets phosphorylated by Lck Fig. 6.14. => PLC-gamma => DAG + IP3 => Ras-MAPK-AP-1, PKC-NFKB, Ca2+-NFAT (nuclear factor of activated T-cells) => IL-2 production => proliferation and differentiation.

Binding => conformational change => signal. Or immunological synapse is formed. Fig. 6.12.

Co-stimulatory receptor: CD28 on naive T-cells bind B7 proteins (CD80 and CD86) on antigen-presenting cells => Ras, Lck, PI3K activation. Fig. 6.28. B7 proteins are induced by IFN

ITAM: Immunoreceptor Tyrosine-based Activation Motif. A motif on signaling molecules initiating a signal from a B/T-cell receptor.

ITIM: Immunoreceptor Tyrosine-based Inhibitory Motif. Motif on inhibitory signaling molecules that reduce or block ITAM signaling.

Chap. 6

Receptors dimerise => JAK => STAT => transcriptional changes

Shut-down of signaling: Dephosphorylation of receptor

A functional pre-BCR (and pre-TCR) leads to down-regulation of RAG-1 and -2, targets RAG-2 for degradation and reduce RAG access to heavy chain locus (beta chain locus)

~p. 267 and p. p. 285

A cell is anagiesed if it reacts with self-antigen in large amounts (such as a souble antigen). The cell produces low amount of receptor and dies within days. For B cells, homing to the peripheral lymphoid organs is impaired.

p.272 for B-cells 

gamma:delta T-cells

NK T cells

alpha:beta T-cells

beta chain genes, gamma chain genes and delta chain genes are rearranged simultaneously. If a functional gamma:delta TCR is produced before a functional beta:pTalpha TCR, the cell becomes a gamma:delta T-cell.

alpha chain rearrangements delete delta chain genes.

fig. 7.22

Double-negative cells develop into double-positive cells in thymic cortex. These can only be rescued from apoptosis by positive selection. First, the expression of both CD4 and CD8 is downregulated, then, CD4 is upregulated again: strong signal through CD4 - Lck => CD4 T-cells, weak signal => CD8 T-cell.

Recognition of self-MHC molecule with CDR1 and CDR2 loops of TCR. Both MHC I and II are expressed on stromal epethelial cells. Co-stimulatory molecule is important since T-cells that bind to MHC I => CD8 T-cells and T-cells that bind to MHC II => CD4 T-cells. In both cases, too strong or too weak binding => apoptosis.

p. 190->

Developing thymocytes are killed if they react to strongly to self-antigen presented by dendritic cells, macrophages and epithelium in the thymus. Tissue-specific antigens from tissue other than thymus is also expressed (controlled by the AIRE gene).

p. 296

They probably happen simultaneously, since the 2 processes involve binding to the same molecules. Each process has its own signalling events.

strong binding => apoptosis (negatively selected)

weak binding => ok (positively selected)

no binding => no signals = apoptosis

p. 296

Follicular dendritic cells are not derived from the bone marrow. They located in the follicles of the white pulp in the spleen (see p. 21). They have long processes that are in contact with B-cells in the follicle. They catch antibody:antigen:complement complexes in the blood and present them to B-cells.

p. 299

Dendritic cells in the T-cell zone of the white pulp in the spleen.

p. 300

If there is no inflammation present to ensure the activating cytokines and co-stimulatory signal, the cell will be anergiesed.

T-cells: Need MHC:peptide-TCR, CD4/CD8 binding to MHC, cytokines (IL-2, depending on efector type)

B-cells: Need MHC:peptide-BCR, CD4 (on T helper cell) binding to MHC, CD40 (B-cell) -CD40L (T-cell) , IL-4

No activation => anergy and increased tolerance to self

p. 303

It expresses low levels of surface Ig and cannot enter lymphoid tissue. It dies within 3 days.

~p. 304

It is a subset of B-cells express other surface proteins than other B-cells). They have a limited BCR repertoire which preferably binds to common environmental pathogens => quick response

p. 306

They recieve surviving signals from interaction with self-MHC:peptide and cytokine IL-17

p. 307

What characterises lymphoid tumors?

What is the difference between leukemia and lymphoma?

Different developmental stages give rise to different tumors. The tumors often arise because of translocation between antigen receptor genes and oncogene (rearrangements of antigen receptor genes make tham succeptible to translocations)

Leukemia: blood-bourne, lymphoma: tissue-resident.

CD8 cytotoxic T-cell: main function: to kill virus-infected host cells

CD4 T-cells:

Th1: Main function: to activate macrophages with intravesicular population of pathogens, secondly: to activate B-cells to produce opsonising antibodies. Induced by: IL-12 and IFN-gamma. Produce: IL-2, IFN-gamma.

Th2: Main function: To activate B-cells to produce hummoral immunity (IgM, IGA and IgE). Induced by: IL-4. Produce: IL-4, IL-5.

Th17: Main function: To help augment neutrophil response. Induced by: TGF-beta, IL-6. Produce: IL-6, IL-17.

Treg: Main function: Regulation of T-cell response. Induced by: TGF-beta. Produce: TGF-beta, IL-10.

Fig. 8.1 and 8.29

Naive T-cells express CCR7, receptor for CCL21, a chemokine from lymph nodes. High endothelial venules (HEV) bind CCL21 on cell surface and have upregulation of adhesion molecules.

Chap. 8

There is a gradient of S1P with more S1P in blood than in lymph node. Naive T-cells express S1P receptor, if they are not trapped by antigen binding in lymph node, the gradient will draw them to the blood. Trapped T-cells lose S1P receptor expression

p. 330

Plasmacytoid dendritic cell: senses viral infection with TLR-7 and -9 in endolysosomes (detects viral RNA and DNA) => IL-12 production (NK cell activation) and IFN alpha -beta production

p. 340

Dendritic cell is killed by CD8 T-cell or Th1 cell (Fas ligand). Pathogen is released and can be taken up by fresh phagocyte.

Chap. 8

1) TCR-MHC:peptide => activation

2) CD28 (T-cell) -  B7 (co-stimulatory molecule on activating cell) => IL-2 and IL-2R expression => survival

3) cytokines: IL-6, IL-12, TGF-beta => differentiation

Fig. 8.19

CD8 T-cells need more co-stimulatory signal. Th-cells can by binding CD40L to CD40 on APC induce higher expression of co-stimulatory molecule (B7) to activate the CD8 T-cell.

p. 352

Natural Treg inhibits in a contact-dependent manner and by secreting IL-10 and TGF-beta

p. 354

IL-10: reduce IL-2, TNF-alpha and IL-5 expression in T-cells. And reduce production of MHC and co-stimulatory molecules.

TGF-beta: block cytokine production, cell division and killing ability of T-cells.

p. 355

Initially, CD8 T-cell binds with adhesion molecules to potential target cell => time to try if the cells MHC I:peptide binds to TCR. If no, cell is released; if yes, LFA-1 (T-cell) and ICAM(target cell) binds tightly and clusteres together with the TCR-MHC-CD8 complex => immunological syneapse = focused area for release of cytotoxins.

Perforin: delivers effector molecules to cytoplasm of target cell

Granzyme: Protease that cleave caspase-3

Fas ligand: induce apoptosis by extrinsic pathway

~p. 359

IL-4

Fig. 8.33

1- IFN-gamma, induces MHC I and II on the activated cell

2- CD40 ligand (to bind CD40

focused release of IFN-gamma is very important, because extensive macrophage activation => huge energy consumption + tissue damage by ROS and NO

p. 370

Granulocyte-Macrophage-Colony-Stimulating-Factor stimulates development of new macrophages, granulocytes and dendritic cells in bone marrow

fig. 8.34

Release TNF-alpha that activates endothelium.

Creates CXCL2 gradient to guide migrating cells

p. 372

Co-receptor consists of CD19, CD21 and CD81. CD21 binds complement (C3d and C3g). Since the complpement component is linked to the antigen, this brings the BCR and the co-receptor close together => stronger signal

p. 382

A T-cell and B-cell must be activated by same pathogen, they have linked recognition, they are cognate. This help prevent self-reaction, since both self-reacting T-cell and B-cell must be present for this to occur.

p. 384

Clonal expansion is proliferation of an activated B-cell in a primary focus or germinal center. It is induced by activation (= IL-4 and CD40L from Th2 T-cells)

~p.384

Adhesion molecules and CCR7 are upregulated => migration into nearest lymph node. It has 24 h to find a cognate T-cell. A cognate T-cell might be in nearest lymph node where dendritic cells present antigen to T-cells. If B-cell finds cognate T-cell, they migrate from T-cell/B-cell boundary to medullary chord to generate primary focus (the function of a primary focus is to produce a rapid Ab response). Later, the cells migrate to a primary follicle near the cortex to produce a germinal center. The same happens in spleen, primary center at red pulp boundary.

p. 387

In a germinal center, activated B-cells proliferate and their BCRs undergo somatic hypermutation to increase affinity for the antigen and class switching. More antigen is brought in by dendritic cells.

p. 388

The mutation rate of the replication machinery is increased in the V-region of the BCR to 1 in 10^3 => even distribution of point mutations. Positive and negative selection ensures that increased affinity is favoured. A higher affinity => signals for survival and proliferation (through BCR-antigen binding, CD40-CD40L binding and MHC:peptide-TCR:CD4 binding)

p. 391

Cytokines produced by T-cells determine class switching of BCR genes.

Th1 T-cell: IFN-gamma => IgG

Th2 T-cell: IL-4 => IgG, IgE; IL-5 => augments IgA production; TGF-beta => IgG, IgA

Fig. 9.13

The cytokines induce transcription leading to opening of DNA helix which creates room for the recombinase proteins: AID + DSB repair proteins.

The plasmablast undergo somatic hypermutation, has surface Ig, has surface MHC II, secrete Ig, proliferates and undergo class switching. All of this but Ig secretion is inhibited by expression of BLIMP-1. Plasma cell may reside in lymph node or migrate to bone marrow

p. 396

TI-antigens are non-protein pathogen components that elicit a B-cell response (lipid and sugar)

TI-1 are B-cell mitogens that by binding to PRR (PAMP receptors) in high conc. produce polyclonal response, by binding to PRR and BCR in low conc. produce monoclonal B-cell response.

Example: LPS

TI-2 are highly repetitive causing many BCRs on one cell to be activated. Too few epitopes => no activation; too many epitopes => anergy.

Example: Highly glycosylated bacteria that is protected from phagocytosis

p. 397

IgM: In blood. Primary binding of pathogen/toxin.

IgD: In blood. Maturation signal in B-cell development. Low levels in blood.

IgG: Überall. Opsonising.

IgA: In mucus. Prevent pathogens to bind to epithelial cells of mucosal surface.

IgE: Under body surfaces. Trigger release of granules from mast cells, basophils and eosinophils.

Chap. 9

IgA is produced by plasma cells in lymph nodes and bone marrow => monomer IgA; and by plasma cells in lamina propria => dimeric IgA

Dimeric IgA (the two IgAs are joined by a J chain) is transcytosed across the epithelium by poly-Ig receptor. Upon release, the receptor cleaves itself to produce a secretory component which is associated with the IgA, protecting it from degradation and binding it to the mucus.

p. 402

IgG - through the placenta (mechanism similar to IgA transport across epithelium)

IgA - in the milk

~p. 403

2 peptide chains: 1 for binding host cell receptor (entry) and 1 for damaging host cell

p. 404

IgM: The pentameric antibody undergoes a conformational change when binding a pathogen leading to exposure of binding sites for C1q and thereby activating the classical complement pathway.

IgG: When more IgG antibodies bind a pathogen it creates bindingsites for C1q and the classical complement pathway is initiated.

Fig. 9.28

Small, soluble antigens are bound by IgG, but if there is not sufficient binding capacity to activate Fc-gamma receptor on macrophages, complement is activated leading to binding of C3b and C4b on the antigen. These components can be recognised by CR1 on erythrocytes and carried to the liver or spleen where macrophages engulf them.

Fig. 9.29

When IgG binds to an antigen presented by a virally infected host cell, the NK cell will kill the cell by Antibody-Dependent Cell-mediated Cytotoxicity (ADCC)

p. 412

2 of the Fc-gamma receptors have ITIMs => inhibition of cell

Fig. 9.30

Mast cells in submucosal layer induce muscular contraction.

p. 415

CONGRATULATION!

You are customer no. 100! YIPPEE!

Initial pathogen recognition by dendritic cells cause them to produce IL-6 and TGF-beta. In absense of IL-4, IFN-gamma and IL-12 => Th17 T-cells develop.

They produce IL-17 which induce cytokine production by local cells: IL-6, CXCL8, CXCL2, GM-CSF (neutrophil recruitment) and antimicrobial peptides

p. 426

Dendritic cells present self-peptide to T-cells and produce TGF-beta. If T-cell reactsto antigen and no other cytokines are present (no inflammation) it becomes an adaptive regulatory T-cell.

(Natural regulatory T-cells are committed in thymus)

p. 427

Upon encountering a pathogen, macrophages and dendritic cells produce IL-12 and NK cells and CD8 T-cells produce IFN-gamma => Th1 cell development.

IFN-gamma inhibits Th2 cell development

p. 428

Parasites, bacteria and other extracellular pathogens induce NK cells to produce IL-4 and dendritic cells to produce IL-10. IL-6 is already present (produced by Th17 cells early in infection) => Th2 cell development.

Th2 cells produce IL-4 = positive feed back

p. 429

Without inflammation, dendritic cells are not activated (= does not express co-stimulatory molecule B7), only present antigen => CD4 T-cells must activate dendritic cells which can then activate CD8 T-cells.

When inflammation is present, dendritic cells express co-stimulatory molecule B7 and cen therefore activate CD8 T-cells by them selves.

p. 435

Dendritic cells produce IL-12 and IL-18 which cause naive CD8 T-cells to produce IFN-gamma which has effects on tissue cells against infection

p. 437

Memory B-cells have never been effector cells, whereas memory T-cells are effector cells that have turned into memory cells

p. 445->

IL-7

~p. 451

M cells continually take up particles from lumen. Dendritic cells engulf them and present the antigens to T-cells or they migrate to a lymph node.

p. 465

Aaaall over. 10 % of epithelium is is intraepithelial lymphocytes, mostly CD8 T-cells

~p. 472

Dendritic cells activating T-cells imprit them with receptors for mucosal tissue

p. 469

Epithelial cells express TLR-5 on basal side and have specific sensors in cytoplasm => production of cytokines, chemokines and antimicrobial agents

Chemokines lead to recruitment of inflammatory cells and lymphocytes

p. 479

The cells produce MIC molecules (MHC-like) that are recognised by NKG2D on NK cells which are then activated for killing

p. 479

Infection through an M cell leads to phagocytosis by macrophages and consecuently TNF-alpha production. TNF-alpha induce inflammation including activation of epithelium leading to loosening of tight junctions which enable the pathogen to invade the tissue further. However, macrophages produce IL-12 and IL-18 and T-cells produce IFN-gamma which enhance macrophage function

p. 480

When T-cells react to non-pathogenic peptides (such as food or commensal bacteria) they are anergiesed, deleted or turned into Treg cells (=Th3 cells). The latter produce IL-10 and TGF-beta which inhibit immune functions

p. 483

- IL-13 induce epithelial cell repair and mucus production

- Th2 recruits and activates eosinophils

- drive class switching of B-cells to IgE

- IL-3 and IL-9 recruit mast cells

p. 486

Helminths secrete molecules that induce Treg development

p. 488