Histiocytes

Subsets = macrophages and various dendritic cell lineages

Granulocyte-Macrophage colony stimulating unit (GM-CSF)

Macrophage colony-stimulating factor (M-CSF)

Blood monocytes can differentiate into either macrophages

under the influence of M-CSF or into DCs under the influence of GM-CSF and IL-4

TGFb1

Epidermal keratinocytes constitutively secrete TGFb1 which promotes the differentiation of LCs from dermal CD14+ precursor cells

These precursor cells upregulate C-C chemokine receptor 6 (CCR6) and migrate into the epidermis to become immature epidermal-resident LCs in response to macrophage inflammatory protein 3 alpha

CD1a

Major Histocompatibility complex (MHC) class I and class II

Interstitial DCs express CD1a, CD11c, CD11b (subset), and MHC class II.

Dermal DCs are of interstitial type and they also express

CD90 (Thy-1).

Identification of macrophages in tissues relies on immunophenotyping. Macrophages differentially express

beta-2 integrins in normal tissues (in most tissues, macrophages express CD11b/CD18).

Other markers used for the identification of macrophages include Mac387 (calprotectin), MHC class II, CD163, and CD204.

Expression of CD4 by neoplastic histiocytes has not been observed in HS.

In comparison, histiocytes in canine reactive histiocytoses regularly express CD4, which indicates an activation phenotype

IgG

Longest half life and the only class with placental transfer

Two mu chains combined with either two kappa light or two lambda light chains.

The secreted form is a pentamer with five, occasionally six, of the four chain monomers linked in a circle by disulfide bonds. There are 10 identical binding sites present.

*Mu chains contain additional CH4 region with complement activation site that is not found in game a chains and do not contain a hinge region*

IgM

It is also produced in secondary responses but is often masked by IgG production.

It is secreted by plasma cells mainly located just under body surfaces.

Walls of the intestine, the respiratory tract, the urinary system, the skin and the memory gland.

Predominates in secretions.

variability is most pronounced in the N-terminal domain of both white and heavy chains.

Called the variable regions V_L or V_H.

Other domains are relatively constant and called constant regions C_L or C_H.

Heavy and light chains are arranged in parallel with each variable heavy domain always beside a variable light domain.

Crystallizable fragment.

The carboxyl terminal ends of both heavy chains with your health together by disulfide bonds. These are structurally identical for many immunoglobulins.

Most of the secondary immune functions of immunoglobulins come from this region (ability to bind compliment and bind Fc receptors on many types of cells).

Critically involved in the effector phase of inflammation and immune response.

Activates T cells to produce IL-2 and up regulates IL-2 receptors

induces fever lethargy sleep and anorexia

Induces secretion of IL-6 from macrophages, hepatocytes and other cells

Shares many biological activities with TNF alpha

Many activities, including inducing Ig secretion from B cells (Induces B lymphocytes to develop into plasmacytes), induction of acute phase proteins in the liver, stimulation of B cell growth, maturation of megakaryocytes, neuronal differentiation, osteoclast activation.

Promotes T cell activation, growth and differentiation

Stimulates the production of IL-1 but can also repress production of IL-1 and TNF alpha while also stimulating production of IL-1RA

Activates NK cells and serves a counter regulatory role in allergy

Potent activator of TH1 lymphocytes

A heterodimer consisting of the P 40 subunit and the P 35 subunit. The P 40 subunit is similar to soluble IL-6R where the P 35 subunit is very similar to IL-6.

Homodimer’s of the P 40 subunit are inhibitory because they bind the IL-12R without activating signaling

Similar action as IL-18 and IL-23 (Synergises with to promote IFN-gamma production)

Important in protection against extra cellular bacteria and fungi

very important in the inflammation associated with autoimmune diseases

induces the production and release of TNF alpha, IL-1 beta and IL-6 as well as chemokines, including IL-8 (mobilizes neutrophils!). Also up regulates ICAM-1 and MHCII on keratinocytes

Kills some tumor cells, regulates adhesion molecules on endothelial cells, induces increased side a kind and inflammatory mediators production by target cells and activates neutrophils

Considered a major pro inflammatory molecule involved in many inflammatory dermatoses

Active molecule is a trimer that is cleaved off the cell surface to be secreted… Can activate target sells while still remaining on the cell surface of the producer cell.

Lymphocytes

Important in the development an organization of peripheral lymphoid organs (spleen and lymph nodes)

Acts in a similar manner to TNF alpha

Promotes the development of neutrophil, eosinophil and macrophage precursors in the bone marrow

Enhances the function of these mature cells and prolongs their survival

Regulates the production of monocytes and osteoclasts in the bone marrow

regulates the maturation of macrophages from monocytes

A critical cytokine in the reproductive tract that plays a role in fertility

Regulates the production of neutrophils then enhances the function of activated mature neutrophils and prolongs their survival

Produced by macrophages Fibroblasts and endothelial cells

Acts with Eotaxin and IL-5 to promote eosinophil chemotaxis in allergic disease

released by TH to cells

receptor = CCR3 - Expressed on eosinophils, T cells, Dendritic cells and keratinocytes

Act with RANTES and IL-5 to promote eosinophil chemotaxis in allergic disease

very important in allergic disease of the airway and G.I. tract as well as in AD and allergic drug eruptions

receptor = CCR3 - Expressed on eosinophils, T cells, Dendritic cells and keratinocytes

Attracts T lymphocytes

Considered a Th2 chemokine that is increased in allergic disease

Induced by IL-4 and IL-13 or as a response to TNF alpha and IFN gamma

These molecules have antiviral properties including regulation of MHC I, Inhibition of viral replication, promotion of viral degradation and activation of NK sells

IFN alpha: Made by leukocytes

IFN beta: Made by fibroblasts

IFN gamma: Has the weakest anti-viral activity but is a potent immune modulatory agent that induces up regulation of MHC I and II on APCs, activates macrophages for killing and activates NK cells

IL-28 and IL-29: Anti-viral activity, increases antigen specific production of IFN-gamma

IFN gamma, IL-2, TNF alpha and CCL3

May also produce IL-5, IL-6 and IL-10

IL-2, IL-12, IL-15, IL-18, IFN alpha

Inhibited by IL-10 and TGF-beta

First produced when T cells are activated by antigen or mitogen

Supports T cell development in the thymus, acts as a differentiation factor through the production of IFN-gamma and IL-4, promotes B cell growth and induction of the J chain required for IgM assembly, activates NK cells and macrophages for killing

Considered the OG T-cell growth factor

Has weak antiviral properties but strong immunologic/inflammatory capabilities

Activates macrophages and other antigen presenting cells by upregulating MHC I and II, upregulating NO synthetase, upregulates IL-1 and TNF alpha

critical in the killing of intracellular microbes

enhances B cell maturation and production of antibodies

activates NK cells for killing

T, B and mast cell growth factor

Critical in the induction of the TH to phenotype and for induction of the class switch to IgE and IgG

Recruits cytotoxic eosinophils

Major regulator of eosinophil infiltrations seen in allergic diseases, enhances production of eosinophils in the bone marrow and enhances eosinophil activation and degranulation

up regulates adhesion molecules on eosinophils to promote their migration and stimulates eosinophil attracting chemokines

Primes basophils for histamine and Leukotriene production

Produced by Th2 cells

Lymphocyte development: stimulates proliferation in T & B lymphocytes progenitor cells and promotes growth and mature T cells

Induces the release of IL-1 IL-6 and TNF alpha from blood monocytes

A growth factor for many cells including Th2 lymphocytes and mast cells

Acts on B cells by enhancing IL-4 induced IgE production

Associated with a new subset of cells called Th9 which appear to be important in chronic allergies/atopy

Plays a role in development - facilitates the growth of progenitors for red cells, platelets and leukocytes in bone marrow

Supports T lymphocytes development in the thymus

Believed to play a role in enabling epithelial and innate defenses - promotes production of anti-microbial peptides,

important in wound healing - stimulates keratinocyte proliferation and inhibits keratinocyte differentiation

Two faced cytokine!

Represses inflammation and promotes production of IgA

Promotes fibroblast proliferation (promotes fibrosis), inhibits epithelial cell proliferation, represses cytokine production, represses ROS and RNS produced by macrophages

under the right conditions (IL-1, IL-6, IL-23) promotes the development of TH 17 cells

Secreted in a latent form and must be activated by proteolysis

Represses macrophage class to expression, represses pro inflammatory cytokines production, represses ROS & RNS production, inhibits Th1 cytokine production and NK cell cytokine production

I poster child of anti-inflammatory and immunosuppressive actions

-TLRs play a crucial role in innate immune system by recognizing pathogen associated molecular patterns (PAMPs) derived by various microbes

-TLR signaling appears to be divergent and play important roles in many aspects of innate immune responses to given pathogens

-TLRs are pattern recognition receptors which play a crucial role in initiation of innate immune response by detecting potential harmful pathogens

-number of TLRs varies between species

-principal receptors used by animal cells to bind to the extracellular matrix, they are heterodimers and function as transmembrane linkers between ECM and the actin cytoskeleton.

-A cell can regulate the adhesive activity of its integrins from within.

-leukocyte integrin deficiency identified in dogs and cattle

-integrins involved in immunology disease at the basement membrane zone

-CD designation will have a descriptive name of cell surface molecules providing targets for immunophenotyping of cells

-CD molecules in act in numerous ways to act as receptors or ligands important to the cells

-A signal cascade is usually initiated, altering the behavior of the cells. Some CD proteins do not play a role in cell signaling but have other functions (such as cell adhesion)

-CD16 (Fc gamma receptor 3) we know if important for antibody-dependent cytotoxicity

-primary immunodeficiency disease characterized by recurrent bacterial infections in the presence of marked leukocytosis

-Severely affected infants have recurrent or progressive necrotic soft tissue infections with Staph and gram negative bacteria, periodontitis, poor wound healing, NO PUS formation, leukocytosis and delayed (> 3 weeks) umbilical cord detachment

-Adhesion defects result in poor leukocyte chemotaxis particularly the neutrophil and its ability to form pus and neutrophilia

-CLAD is inherited blood disorder affected Irish setters, the defect in CD18 has been shown to be due to a point mutation (Cys36Ser beta-2 integrin) and can be fatal

-Field of study that looks at how the environment alters gene expression (pollutants, chemicals, drugs, diet)

-Mechanisms look at DNA methylation (e.g. methylation of a promotor can repress transcription)

-Histone acetylation and methylation are affected and alters the wrapping of DNA around histones and therefore whether a gene is active or not

-MicroRNAs are involved

-nuclear steroid receptor

-In presence of air pollutants this receptor gets activated and causes keratinocytes to secrete a molecule called artemin and binds to sensory nerves to stimulate itch and makes a patient scratch

-Damages skin barrier then penetration of antigens occurs and they become susceptible to antigens (enhances susceptibility to AD)- promotes Th2 response

-SSSS is a serious skin infection caused by the bacterium Staph aureus and seen in humans

-Exfoliative toxin is a serine protease (also known as epidermolytic toxins, epidermolysins and exfoliatins) of S. Aureus that targets Desmoglein-1, an epidermal adhesion molecule and results in a split at the granular layer of the epidermis

-Adults with kidney failure are at increased risk for SSSS because they are not capable of clearing the toxin and mortality is very high. It also affects infants and young children and is characterized by acute onset of fever, skin tenderness and erythema, followed by formation of large, flaccid bullae and shedding of large sheets of skin

-This bacterium produces an exfoliative toxin (2 serotypes in humans- ETA and ETB) that causes the outer layers of the skin to blister and peel

-IL-1

-Toll-like receptor

-Gene transcription (NF-kB pathway)

-Apoptosis (Fas-associated death domain, Caspase-8)

-Leukocyte recruitment (Vascular endothelium--> adhesion molecules; IL-8 chemotaxis, Neutrophil activation)

-Self-amplifying cascade: IL-1, TNF-alpha

-Phospholipase-A2---> arachidonic acid cascade--> Prostaglandins, Leukotrienes, Thromboxanes, HETE, etc

-Innate immune signal pathway

-IL-1

-TNF-alpha

-Toll-like receptors

-Any damage to keratinocytes (oxidative, UV radiation, protein kinase C)

• LPS or danger signals bind to the macrophage and cause hyperactivation
• Hyperactivated macrophages secrete TNF and IL-12 which influence NK cells to increase the amount of IFN-gamma that they produce
• More IFN-gamma around means that more macrophages can be primed

• IL-2 is a growth factor produced by NK cells
• NK cells normally don't express the receptor for IL-2 (so they don't proliferate in response to this cytokine)
• During an infection, TNF is produced by macrophages and upregulates the expression of IL-2 receptors on the surface of NK cells
• NK cells react to IL-2 and make them proliferate (in a self-amplification cascade)
• NK cell proliferation leads to more help to defend infection and activate macrophages

• PRR's respond by producing 'battle cytokines'
• PRR's trigger type 1 interferons (alpha and beta)
• INF-α and IFN-β bind to interferon receptors on cells that produce them and binding results in the expression of genes that limit the virus's ability to reproduce in the cells
• INF-α and IFN-β are also warning proteins and when they bind to receptors on nearby unaffected cells, they prepare them for an attack
• The warned cells produce proteins to hinder viral replication but also commit suicide if they are attacked (so both infected cells and viruses within them will be destroyed and limit spread of infection)

• Huge quantities of type 1 interferons when infected by a virus
• pDCs are important innate immune system players in a viral attack

-IFN-γ 

-This cytokine is produced mainly by helper T cells and natural killer cells

• It is a mechanism to help prevent inappropriate B cell activation.
• This process ensures that only B-cells that make appropriate antibodies to defend against invaders will be activated.

• T-cell dependent activation results in affinity matured IgG, IgA, or IgE antibodies

• B cells can change their Fc region by class switching and their antigen-binding (Fab) region by somatic hypermutation
• B cells activated without T cell help (eg. in response to carbohydrates on bacteria surface) generally don't undergo either class switching or somatic hypermutation
• Allowing some antigens to activate B cells without T cell help is important because it allows the adaptive immune system to respond to antigens to include not only proteins but carbohydrates and fats as well
• Most B cells that are activated without T cell help are found in the spleen (these helpless B cells can mount a rapid defense against bacteria such as Streptococcus pneumoniae by making IgM antibodies that recognize epitopes on the polysaccharide capsule that surrounds the bacterium)

• Helper T cells only recognize protein antigens- the peptides presented by class II MHC molecules
• Therefore it is important to allow some antigens to activate B cells without T cell help since many common invaders have carbohydrates or fats on their surface

• Activation of virgin B cell requires 2 keys
• The first key is cross-linking of B-cell receptor and the second key is a co-stimulatory key (CD40L on helper T cell bind to CD40 on B-cell and activate)

• IgM is a great complement fixer, good opsonizer and the first antibody made
• IgA is resistant to stomach acid and protects mucosal surfaces and is secreted in milk
• IgG is OK complement fixer, a good opsonizer, helps NK cell kill (ADCC), and can cross the placenta
• IgE defends against parasites, causes anaphylactic shock, and causes allergies

• Somatic hypermutation alters the antigen-binding region of the antibody
• Probability that B-cell will proliferate depends on affinity of the BCR for the antigen

• Class I MHC molecules present protein fragments to killer T-cells
• Class I MHC presents proteins made inside cells and allows CTL's to check most cells in the body for infection
• Most proteins made in pathogen-infected cell remain inside the cell and without Class I molecules they would never be chopped up and displayed for killer T-cells to view (epitopes cannot be hidden from CTL's)

• Class II MHC are "billboards" to alert Helper T-cells that a battle is occurring. 
• Class II MHC pick up molecules from proteins outside the cell but avoid peptides from proteins made inside the cell
• Dendritic cells use class II molecules to display fragments of proteins from out in tissues

• Dendritic cells use class II MHC to display fragments of protein collected in tissues and class I MHC to display fragments of protein made by viruses and bacteria that may have infected dendritic cells in battle site
• Macrophages are activated by danger signals and function as antigen-presenting cells. They do not travel to L.N. to present antigen but instead stay in tissues and battle to keep experienced T cells fired up
• Activated B cells are not useful in initiating an adaptive immune response to new invaders. They use receptors to concentrate as antigen collectors and present to Helper T-cells.

• Dendritic cells take a "snapshot" of front lines and travel to Lymph nodes and present antigen collected at the battle site to virgin T-cells
• Dendritic cells also use class II MHC molecules to display fragments of proteins it has collected out in the tissues and class I MHC molecules to display fragments of proteins made by viruses and bacteria that may have infected the dendritic cells out at the battle site.

• The number of D.C's dispatched from tissue and the number of D.C's recruited depends on the severity of the attack.
• In a serious infection, increased cytokines are produced and increased dendritic cells are activated to travel to lymph nodes which leads to increased dendritic cell recruitment from blood and increased numbers of activated T-cells

• CD4+ co-receptors "clip onto" class II MHC molecules and CD8+ co-receptors will only match class I molecules. CD4 and CD8 co-receptors focus attention on the proper MHC molecules.
• When a TCR is engaged then a T cell receives a co-stimulation and the signal is amplified many times
• B7 molecules provide co-stimulation to T-cells by plugging into CD28 on the T-cell

• Engagement of TCR increased expression of adhesion molecules on the Th cell surface, strengthening the glue that holds the APC and T cell together.
• Initial MHC and TCR binding is weak to allow rapid scanning
• Velcro-like adhesion molecules are important for T cell activation

• Interaction between the dendritic cell and the naive helper T cell is not one way, instead, the cells perform an "activation dance" and stimulate each other.
• A dendritic cell becomes a more potent APC and the Th cell is activated to express a high level of CD40L required for helping activate B cells

• Early in infection, B cells and killer T cells can be activated without the assistance of helper T cells.
• Helpless plasma B cells make IgM antibodies because they have not switched to a class of antibodies that might be more appropriate to defend against a particular invader.
• B cells have not undergone hypermutation in initial infection and their BCRs are not 'fine tuned' and they only live a short time
• Helpless CTLs do not proliferate robustly and are short-lived and do not kill as efficiently as T cells which receive assistance from helper T cells
• Helpless B and T cells serve to provide a rapid response to pathogens while the more sophisticated B and T cells are being produced.
• T cell help is not required during the initial activation of killer T-cells. A two-cell interaction between a naive CTL and an activated dendritic cell is sufficient. CTL's that are fully activated with the assistance of Helper T-cells can proliferate robustly and may efficiently become memory killer T cells for subsequent invasions

• For naive T cells or virgin CTL to be activated, the T-cell must recognize its cognate antigen presented by an APC
• This fail-safe makes it less likely that a T-cell will turn weapons onto a host (eg. immune-mediated disease)

• IL12 producing dendritic cells --> presents battle antigens to virgins T-cell --> Helper T-cell produces "classical" Th1 cytokines (TNF, IFN-gamma, and IL-2). Useful in viral or bacterial attack in tissues
• IL4 will cause naive Th cell to become Th2 cell and produce IL-4, IL-5, and IL-13 (recognize worms or bacterial pathogens). Dendritic cells still need to activate naive Th cell in L.N. (D.C. does not produce initial IL-4- unsure of exact source)
• IL17 (Fungal and extracellular bacteria)- D.C. produces TGF-B, IL-6, and IL-23 --> activates newly activated helper T-cells to produce IL-17 subset of cytokines (IL-17, IL-21, and IL-23)

• Th1 cells produce IFN-gamma that influences B-cells during class switching to produce IgG3 antibodies (good at opsonizing viruses and bacteria and fixing complement)
• Th2 cells produce IL-4 which is a growth factor for B-cells and influences B-cells to class switch and produce IgE antibodies. Th2 cells also produce IL-5 which encourages B cells to produce IgA antibodies (useful against bacteria in the GI tract)
• Th17 cells produce IL-21 that causes B-cells to protect mucosal surfaces to produce IgG3 and IgA antibodies. IgG3 is an antibody isotype good at activating complement cascade on the surface of bacteria

• Th1 cells secrete TNF which helps activate macrophages and NK cells. Macrophages are only activated for a limited amount of time
• IFN-gamma produced by Th1 cells will keep macrophages "fired up"
• NK cells will "tire out" in about 16 hours and IL-2 produced by Th1 cells will recharge NK cells so they can keep killing
• IL-2 is also a growth factor to stimulate the proliferation of CTLs, NK cells, and Th1 cells

• Cytokines have a short-range and provide local effects
• This allows immune system to defend against different types of invaders which attack different parts of the body

• 2 different ways cells can die (necrosis vs apoptosis)
• Cells die via necrosis as a result of a wound or when killed by a virus or bacteria
• Enzymes or chemicals contained with cell are released during necrosis and damaged tissue
• Death by apoptosis is "tidier" and contents of cells are enclosed by vesicles and destroyed by nearby macrophages ("garbage collectors")
• CTLs that kill targets via apoptosis do not cause collateral damage

• Lymph node: highly organized with areas of APC's, T-lymphocytes, B-lymphocytes, and macrophages
• Peyer's Patch in Small Intestine: M cell in the lumen of SI initiates an immune response to pathogens that invade the intestinal tract. 
• Spleen: one of the areas of the body where B cells can be activated without Th cells ("marginal zone B cells")

• Lymph Node: High Endothelial venules in paracortex- B and T-cells pass through this area when arriving in blood
• Peyer's Patch: Have HEV through which lymphatics can enter the blood via "M cell"
• Spleen: In contrast to L.N's and Peyers Patch where everything enters from HEV (for B and T cells), the spleen is an open-house party from blood.

• Secondary lymphoid organs (Spleen, L.N. and Peyer's Patches of SI) play critical roles in immunity by creating an environment in which antigen, APC's and lymphocytes can gather to initiate an immune response
• To help make this happen, the secondary lymphoid organs are "compartmentalized" with special areas where T cells or B cells are "preselected" before they actually are allowed to meet.

• Within an L.N., the movements of lymphocytes and dendritic cells are carefully choreographed through the use of cellular adhesion molecules which are up and downregulated as cells travel through node
• As a result, helper T cells which were activated in the T cell areas, move to the boundary of the B cells area to meet with B cells which have recognized their cognate antigen displayed by follicular dendritic cells
• T and B cells do a "dance" during which helper T cells become fully "licensed" to help the B cells produce antibodies
• Licensed Th cells are called follicular helper T cells (TfH cells)

• Virgin killer T cells circulate through the blood, lymph, and secondary lymphoid organs and may be activated if they encounter their cognate antigen displayed by class 1 MHC molecules on the surface of antigen-presenting cells in the T cell zones of the secondary lymphoid organs. If it does then it will proliferate and recirculate to secondary lymphoid organs or leave the circulation and enter inflamed tissues to kill cells infected with viruses or other pathogens (eg. intracellular bacteria)
• Virgin B cells also travel to secondary lymphoid organs looking for their cognate antigens.
• If in lymphoid follicles of the secondary lymphoid organs, a lucky B cell finds the antigen to which its receptor can bind then it will migrate to the border of the lymphoid follicle. There, if it receives the required co-stimulation from an activated helper T cell, the B cell will be activated and will proliferate to produce many more B cells that can recognize the same antigen

• "Experienced" Th cells have adhesion molecules on their surface that encourage them to re-enter the same type of lymphoid organs in which they were activated (e.g. a Peyer's patch or peripheral lymph node)
• This will spread activated Th cells around to those secondary lymphoid organs in which B cells or CTLs are likely to be waiting for their help
• Recirculating Th cells also can exit the blood vessels that run through sites of inflammation
• Th cells provide cytokines that strengthen the reaction of the innate and adaptive systems to attack and which help recruit even more immune system cells from the blood
• In the germinal center, B cells may class switch to produce IgA, IgG, or IgE antibodies, and they may undergo somatic hypermutation to increase the average affinity of their receptors for antigen

• another type of CD4+ T cell exposed to an environment rich in TGF-B  can be "induced" to become iTregs
• Inducible regulatory T cells are called "regulatory" because instead of secreting cytokines such as TNF and IFN-gamma, which activate the immune system, iTregs produce cytokines such as IL-10 and TGF-B that help restrain the system
• IL-10 binds to receptors on APCs and reduces PRRs expression and makes it more difficult for APCs to be activated
• TGF-B produced by iTregs reduces the proliferation of T cells and makes killer T cells less vicious killers

• In addition to engaging stimulatory CD28 molecules on T cells, B7 proteins on APCs also can plug into other receptor proteins on T cells called CTLA-4 (the bulk of CTLA-4 is stored inside the cell)
• About 2 days after virgin T cell activation, an increased amount of CTLA-4 is moved from intracellular reservoir to cell surface
• B7 on antigen-presenting cells binds to CTLA-4 with an affinity thousands of times higher than its affinity for CD28 (so with time CTLA-4 will outcompete CD28 for B7 binding)
• Early in infection B7 on the surface of APC binds to CD28 on the surface of T-cell as a co-stimulator to activate T-cell. However, after the battle has been going on for a while, limited B7 proteins on APCs will bind mainly to CTLA-4 and not CD28 (harder to reactivate T cells and helps shut down the adaptive immune response)

• Late in infection, CTLA-4 on T-cell "soaks up" B7 co-stimulatory proteins on APCs and makes reactivation of T cells less efficient
• Ligation of PD-1 inhibits the function of previously activated T cells. Programmed death 1 (PD-1) helps deactivate T-cells (expression of PD-1 on the surface of T cells increases after activation and the ligand for PD-1 (PD-L1) appears on the surface of many different cell types in tissues that are under the attack (inflamed tissue)
• When PD-L1 protein on inflamed tissues binds to PD-1 on T cells that have been at work for a while, the T cells become "lethargic" and don't function well to decrease collateral damage from not restraining T cells

• These "negative regulators" make it more difficult to reactivate T cells (CTLA-4) or make T cells function less well (PD-1)
• Need strong functioning T cells to fight cancer

• Two tests administered CD8 co-receptors only bind to class I MHC molecules, and CD4 co-receptors only bind to class II MHC molecules
• Thymic medulla second test administered for tolerance of self (negative selection)
• T cells with receptors that do recognize the combination of MHC molecules and self peptides are deleted. Second test which eliminates T cells that could react against our own antigens is crucial otherwise autoimmune disease may result.

• Final result of thymus testing is T cells that have receptors which do recognize self MHC-peptide complexes presented by cortical thymic epithelial cells but which do NOT recognize self antigens presented by MHC molecules on thymic dendritic cells or medullary thymic epithelial cells
• "Thymic graduates" that pass these tests express high levels (ie. many molecules) of the T cell receptor on their surface plus either the CD4 or CD8 co-receptor but not both

• Positive selection (survival) of T cells results from a relatively weak interaction between TCRs and MHC-self peptide displayed on cortical thymic epithelial cells (an interaction that is strong enough to insure that the TCRs are focused on presented antigen)
• Interaction between TCRs and MHC-self peptide expressed on medullary thymic epithelial cells or thymic dendritic cells must not be too strong or cell death results (negative selection)
• After T cells leave the thymus, the interaction between their TCRs and MHC peptide displayed by professional presenting cells must be strong enough to trigger activation

• It is possible that the "wiring" within the T cell changes as the T cell matures
• These differences in TCR density and signal processing could influence the interpretation of signals generated by the various types of sender cells
• co-stimulatory molecules- and co-stimulatory signals could change the meaning of the signal that results from TCR-MHC-peptide engagements

• The traffic pattern takes virgins to the areas of the body where they are most likely to encounter APCs  and be activated
• The result of the traffic pattern followed by virgin T cells, most T cells that could be activated by an abundant self antigen in the secondary lymphoid organs already will have been eliminated by seeing that same, abundant self antigen in the thymus

• Self antigens that are too rare to efficiently delete B cells in the bone marrow usually are too rare to activate these B cells in the secondary lymphoid organs
• Traffic pattern of virgin B cells which restricts them to circulating through the secondary lymphoid organs, helps protect them from encountering abundant self antigens that are not present in the bone marrow
• Virgin B cells that venture into the tissues can be anergized or deleted if they recognize their cognate antigen but do not receive T cell help

• Plasmacytoid dendritic cells, antigen presenting DCs, folliuclar DCs and thymic dendritic cells
• Plasmacytoid dendritic cell (pDC) look like plasma cells, but have certain characteristics similar to myeloid dendritic cells, use TLR 7, TLR 9
• Conventional dendritic cell (previously called Myeloid dendritic cell) (cDC or mDC). Secrete Interleukin 12 (IL-12), Interleukin 6 (IL-6), TNF, chemokines. Use TLR 2, TLR 4. Most similar to monocytes. mDC are made up of at least two subsets:
  (1) the more common mDC-1, which is a major stimulator of T cells
  (2) the extremely rare mDC-2, which may have a function in fighting wound infection. 
• Lymphoid and myeloid DCs evolve from lymphoid and myeloid precursors, respectively, and thus are of hematopoietic origin. By contrast, follicular dendritic cells (FDC) are probably of mesenchymal rather than hematopoietic origin and do not express MHC class II, but are so named because they are located in lymphoid follicles and have long "dendritic" processes.

• cell-mediated immune response
• antagonize Th2 responses to a certain extent
• Atopic diseases were originally considered to involve a Th2-Th1 imbalance
• Th2 cytokines predominate during sensitization and in acute lesions of AD
• T-Helper 1 responses contribute to the development of clinical disease and may predominate in chronic lesions

• Innate immune system is "hard wired" memory which defends us against everyday defenders
  • TLRs used to detect broad classes of microbial pathogens
  • receptor genes passed down from generation to generation
• Adaptive immune system is set up to remember the specific attackers we encounter during our life
  • B and T cells begin life with blank memory
  • During an attack, pathogen specific B and T cells build up their numbers but a few remain as memory B and T cells to protect against subsequent attack by same invader

• B cells and the antibodies they produce confer life-long immunity to infection
  • 3 kinds of B cells are generated (short lived plasma B cells, long-lived plasma cell and central memory B cell)
  • generation of short and long-lived memory B cells require T cell help
  • Central memory B cells function as memory "stem cells" which slowly proliferate to maintain a pool of central memory B cells
• After naive T cells have been activated in response to attack, they proliferate and build up their numbers as much as 10,000 fold to give them passports to travel out to the tissues to do battle with the enemy
• Overall, memory B and T cells are better able to deal with a second attack because they are much more numerous than before the first invasion and because they are more easily activated than virgin B and T cells

• Naive T cells become activated and proliferate---> receive passports to travel out to tissue to battle enemy---> become effector T cells- 90% of the effector T cells die by apoptosis but some of them become tissue resident memory T cells
• Tissue resident memory T cells remain at the scene of the original battle and wait to pounce if we are attacked again in the same area of the body
• Other T cells which responded to the initial infection become effector memory T cells, circulate through blood and lymph and some memory T cells remain in the secondary lymphoid organs (central memory T cells)---> central memory T cells activate quickly during subsequent attack and remain in secondary lymphoid organs waiting for another attack by same organism

• B cells can fine-tune their receptors through somatic hypermutation. T cells cannot
• There is no T cells equivalent of the long-lived plasma B cell
• The weapons made by B cells (the antibody molecules) continue to be deployed even after an invasion has been repulsed
• Th1, Th2, Th17 cells function to turn on the immune system and have long memories
• iTreg cells turn off the immune system once the battle has been won
• T cells take a 3 prong approach. If invaders return to infect the same area of the body, the tissue-resident memory T cells are there to greet them. On the other hand, if invaders attack a different part of the body, the effector memory T cells are patrolling those areas to provide protection. And central memory T cells are standing by in the secondary lymphoid organs to provide backup. It is not known how long each type of memory T cells persists after an attack
• T cell memory usually lasts a decade

• Innate system remembers invaders that its hard-wired receptors recognize
• Memory B and T cells are better able to deal with a second attack because they are much more numerous than before the first invasion, and because they are more easily activated than are virgin B and T cells
• Long-lived plasma B cells, which reside in bone marrow, continuously produce moderate amounts of pathogen-specific antibodies (antibodies produce immediate protection if we are attacked again)
• Central memory B cells are a pool of long-lived plasma cells which proliferate slowly in the secondary lymphoid organs between invasions
• Tissue resident memory T cells remain at the scene of original battle to attack in the same area of body, effector T cells circulate through blood and lymphatic systems and central memory T cells persist in the secondary lymphoid organs following an attack. Central memory T cells react quickly and respond, proliferate and mature into effector T cells

• B and T cells of the adaptive immune system have updatable memories which can remember the individual invaders we have encountered during our lifetime
• As a result every person have a different adaptive memory
• Memory B and T cells are better able to deal with second attack because they are much more numerous than before the invasion and more easily activated than virgin B and T cells

• intestinal immune system is under constant attack by bacteria and other invaders (commensal vs pathogenic bacteria which breach epithelial barrier are intercepted by resident macrophages)
• "default option" for the intestinal immune system is anti-inflammatory
• inducible regulatory T cells- special Th cells whose job is to limit inflammation 
  • present in huge numbers in lamina propria

• healthy intestinal epithelial cells produce TGF-B, a cytokine which encourages Th cells that are activated in the intestinal environment to become iTregs 
  • Some commensal bacteria produce butyrate (short chain fatty acid) that influence Th cells to become regulatory T cells
• T cells then give off cytokines such as TGFB-B and IL-10 to help "calm" the mucosal immune system
• many CTLA-4 checkpoint proteins expressed on the surface of iTreg cells can bind to and "mask" B7 proteins on antigen presenting cells in the lamina propria and decrease the APC's ability to activate effector T cells
• commensal bacteria contribute to help maintain normal immunosuppressive environment in the lamina propria

• IgA antibodies in the lamina propria can bind to invaders, transcytose epithelial cells with their cargo and usher intruders back out into the intestine for disposal
• secretory IgA does not cause inflammation
• IgA antibodies can deal gently with intestinal invaders without causing inflammation
• Retinoic acid produced by intestinal dendritic cells can drive IgA production
• In most cases, class switching requires help from Th cells 

• Healthy intestinal epithelial cells produce cytokines which help keep the intestinal immune system relatively calm
  • these cytokines induce helper T cells to become regulatory T cells
• If no danger, and things just need to be calm then the lamina propria DCs don't produce IL-6 and naive Th cells (under the influence of tissue-produced TGF-B) become iTregs
• If there is an invasion of pathogenic bacterial that have flagella, dendritic cells produce IL-6, which cause helper T cells to commit to becoming Th17 cells

• Dendritic cells in the lamina propria continuously evaluate danger posed by current invaders
• serious breach of epithelial barrier will result in intestinal immune system switching from a gentle response to an aggressive reaction
• Altered dendritic cells can instruct helper T cells to become Th1 or Th17 cells
  • Helper T cells orchestrate an inflammatory response in which formerly non-inflammatory macrophages become "angry" and neutrophils are recruited from the blood to engage invaders in hand to hand combat
• Commensal and pathogenic bacteria share many molecular features so it is unknown how dendritic cells distinguish between the two types
  • likely that bacteria trigger different combinations of pattern recognition receptors (PRRs) leading to different outcomes

• Interaction of IgE antibodies with white blood cells or mast cells ---> mast cell degranulation is central event in allergic reaction
• Atopic individual exposed to allergen (eg. pollen) and produce large amount of IgE which recognize the allergen
• Allergens are small proteins with repeating structure and IgE bind close together
• Second or subsequent exposure---> an allergen can crosslink the IgE molecules that are bound to surface  ---> clustering of IgE receptors tells mast cells to degranulate
• Mast cell granules contain histamine and other powerful chemical and enzymes

• Atopic individuals produce more IgE antibodies because their allergen specific helper T cells tend to be of the Th2 type
• B cells tend to change to IgE production if class switching takes place in germinal centers that contain Th2 cells which secrete IL-4 and IL-5
• Decision to produce IgG and IgE in response to allergen depends on type of helper T cells present in the secondary lymphoid organ which intercepts the allergen
• "early-life education" of immune system will also have a large impact on the health of an individual later in life

• Autoimmunity results when a breakdown in the mechanisms meant to preserve tolerance to self is severe to cause pathological reaction
  • majority of autoimmune diseases occur when the layers of tolerance-inducing mechanisms fail to eliminate self-reactive cells in genetically normal individuals
• Individual must express MHC molecules that efficiently present a peptide derived from target self antigens
  • MHC molecules you inherit can play a major role in determining your susceptibility to autoimmune disease
• Affected person must produce T and in some cases, B cells which have receptors that recognize a self antigen
  • For autoimmune disease to occur- person must have MHC molecules that can present a self antigen and lymphocytes with receptors that can recognize the self antigen
  • also need breakdown of tolerance mechanisms designed to eliminate self reactive lymphocytes

• TCRs that recognize self antigens usually can cross react with multiple environmental antigens
  • viral or bacterial infections may be involved in some autoimmune disorders but it is unlikely that any single microbe is responsible for any one autoimmune disease
• It is not enough for a microbe to activate self reactive T cells my mimicry, there must be an inflammatory reaction going on in the same tissues that express the self antigen
  • As a result of this inflammatory reaction, APCs are activate that can re-stimulate self reactive T cells
  • cytokines generated by the inflammatory response can upregulate class I MHC expression on normal cells in tissues and make these cells better targets for destruction by self reactive CTLs

• The production of memory B and T helper cells does not require that an antigen presenting cell be infected
• B cell receptors recognize an attacker or a fragment of an attacker which has been transported to the secondary lymphoid organs by the lymph or blood for the B cell to become activated
• After a period of proliferation, if T cell help is available then some of the resulting B cells will become memory cells
• Memory B and helper T cells can be produced efficiently even when no immune system cells have been infected by an attacker

• Memory killer T cells can be produced during a microbial attack but the microbe must infect an antigen presenting cell first
• If a virus infects a dendritic cell then the virus takes over the cell biology to make viral proteins---> some of proteins chopped into peptides and loaded onto class I MHC molecules
• As result, killer T cells receptors recognize the virus' peptides will be activated if assistance available from helper T cells and memory killer T cells will be produced

• Killed virus vaccines: many vaccines like the flu vaccine are used to make vaccines against disease causing bacteria. The presence of a few live viruses in the vaccine preparation is not a concern since without vaccine many would become infected. To prepare the vaccine, the toxin is purified and treated with aluminum salts to produce a weakened form of the toxin (called the toxoid).
• Subunit vaccines: non-infectious vaccines that will generate memory helper T cells and B cells (which can make protective antibodies), memory killer T cells will not be made-because antigen presenting cells will not be infected. Not long lasting as protection produced by vaccination with live microbe.
• Attentuated virus vaccines: provided long-lasting immunity because they replicate to a limited extent in the host, thereby mimicking a natural infection. One important feature of attentuated virus vaccines is that they can produce memory killer T cells
• Carrier virus vaccines: newer vaccine preparations use genetic engineering to introduce a new gene (or genes) from a pathogenic microbe into a virus that does not cause the disease ("trojan horse"). Inoculation with a carrier vaccine should generate memory killed T cells that can protect against future attack from a real pathogen. There is no chance that this vaccine will cause the disease it is designed to protect against

• AIDS virus has extremely high mutation rate
• carrier vaccine could generate memory killer T cells without putting the vaccine recipient at risk for a real AIDS virus infection
• Vaccine could be made to elicit broadly neutralizing antibodies in healthy individuals to protect against infection (at least by many common HIV-1 strains)
  • unfortunately, neutralizing antibodies against HIV-1 usually arise years after the initial infection as the result of many rounds of somatic hypermutation

T helper 1 pathway is characterized by the following markers?

a) IL-5, IL13

b) IL-17A, IL-23A

c)IFN-gamma, MX1, CXCR3

• c) IFN-gamma, MX1, CXCR3

• powerful tumor suppressor proteins exist within the cell to prevent cancer cells
• Naive T cells are NOT allowed out into the tissues where they might encounter self antigens that were not present in the thymus during tolerance induction
  • this is to preserve tolerance to self (and avoid autoimmune disease)
  • tolerance normally wins
• If virgin CTL breaks tolerance and enters tissue with tumor antigen displayed by class I MHC molecules on cancer cells, the cancer cell will not provide the co-stimulation the CTL needs for survival (eg. APC cell will provide co-stimulatory molecules like B7---> tumor cells are NOT APCs)

• cancerous blood cells have fewer mutations than solid tumors
• properties of blood cell cancers suggest CTLs may provide surveillance against some of them
• traffic patterns of cancer cells and virgin T cells actually intersect
  • some cancerous blood cells express high levels of B7 and provide necessary co-stimulation

• Both NK cells and macrophages recognize diverse target structures so the chance of them being fooled by a single mutation is small
• macrophages are located out in the tissues where most tumors arise and could intercept cancer cells at an early stage
• Macrophages need to be hyperactivated before they can kill cancer cells
  • this is what BCG treatments do- they hyperactivate macrophages by causing inflammation
• most NK cells are found in blood
  • like neutrophils, NK cells are "on call"
  • the cells that do the calling are macrophages and dendritic cells
  • unless there is an inflammatory reaction, most NK cells just circulate in blood

• It is unlikely that killer T cells provide significant surveillance against most solid tumors in humans
  • there is an activation problem due to safeguards to prevent autoimmunity
• Virgin T cells are activated in secondary lymphoid organs and unlikely to come in contact with cancer cells in tissue
• most cancer cells cannot supply co-stimulation required to activate killer T cells
• Killer T cells have a high mutation rate and cancer cells represent a "moving target"
• rapidly mutating tumor cells create an immunosuppressive environment which can interfere with the immune response and make CTLs ineffective against solid tumors

• Viruses which only cause acute infections do NOT play a role in cancer
  • dead cell isn't going to make a tumor
  • most viral infections are NOT associated with cancer
• All viruses which have been shown to play a role in cancer are able to establish chronic infections and "hide" from the immune system
• Without killer T cells, more cells would likely be infected during a virus attack, thereby increasing the number of cells in which the virus may establish longterm infection
  • likely why immunocompromised people have higher than normal rates of virus associated tumors
• CTLs cannot provide significant surveillance against viral infected cells that have become cancerous

• "Checkpoint" proteins (CTLA-4 and PD-1) appear on the surface of activated T cells to keep them from being over-exuberant
• T cells that have undergone repeated rounds of activation and proliferation express increased amounts of CTLA-4 on their surface
• Checkpoint protein competes with activation receptor CD28 for binding to B7 (expressed on activated dendritic cells)---> makes it harder for T cells to be reactivated in secondary lymphoid organs---> limits ability of tumor specific T cells to build up numbers to point where they are numerous enough to destroy a tumor
• Ligation of PD-1 suppresses the effector function of T cells and the ability to kill target cells and proliferate
• PD-1 blockade seems to cause less serious side effects than CTLA-4 blockade
• Expressing or inducing expression of PD-L1 allows solid tumors to protect themselves and create local environment that is hostile to T cells

• monoclonal antibodies that prevent growth factors from binding to their receptors
  • used to treat several types of cancers
  • Rituximab mAb that binds CD20 protein on B cell surface and marks cells for destruction by antibody-dependent cellular cytotoxicity
  • CD20 expressed on immature B cells but not found on surface of blood stem cells that "restock" blood system
  • Trastuzumab used against metastatic breast cancer to block Her2 receptor and cover it to prevent grow signal
• tumor infiltrating lymphocytes (TILs)-
  • cancerous tissue had been infiltrated by T cells
  • some of the TILs have receptors that recognize antigens expressed by cancerous cells (tumor specific T cells)
  • cultured these cells independently in presence of IL-2 to cause tumor infiltrating lymphocytes to proliferate tumor specific T cells and infused back to patient to treat cancer (adoptive cell transfer)
• checkpoint blockade
  • Two checkpoint proteins (CTLA-4 and PD-1) appear on surface of activated T cells to keep them from being over exuberant
  • checkpoint protein competes with activation receptor CD28 for binding to B7 (expressed on activated dendritic cells) and makes it harder for T cells to be reactivated in secondary lymphoid organs
• CAR T cell therapy
  • use genetic engineering to modify a patient's T cells so they produce an artificial T cell receptor (synthetic TCR)
  • "Carrier virus" including engineered chimeric receptor into genome of infected T cell 
  • virus infected T cell proliferates in the lab and infused back to patient
  • target most successful is CD19 (part of B cell co-receptor expressed on surface of most leukemias and lymphomas)

• Develop from bone marrow precursors
• Express c-Kit (receptor for growth factor stem cell factor)
• vary pending on body location in normal canine skin

• ears/pinnae
• ventral interdigital skin