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- a series of proteins that work in a cascading fashion to generate important host defense mechanisms
- can be activated in 3 ways:
- 1. Classical
- 2. Alternative
- 3. MBL (mannan binding ligand)
Classical Complement Pathway
- triggered by antibodies (Igs) bound to antigens on the microbial surface
- results in the recruitment of inflammatory cells
What are the predominant activators of the classical pathway?
- antigen-antibody complexes
- this pathway is a major effector pathway of the humoral adaptive immune response
Classical Complement Pathway Cascade
- 1. when an antibody binds an antigen fragment, a region on it's Fc (heavy chain) becomes exposed
- Ig switches from a T → Y conformation, exposing its complement binding site
- 2. C1q can now bind to the Ig's Fc
- 3. C1q undergoes a conformational change after binding
- 4. C1r & C1s immediately bind to altered C1q (q → r, s)
- 5. this triad = Activated C1 (C1q,r,s)
- 6. Activated C1 cleaves C4 into C4a (released) & C4b (stays covalently bound)
- 7. C14b binds & cleaves C2 into C2a (released) & C2b (stays bound)
- 8. C14b2b splits C3 into C3a & C3b
- 9. C14b2b3b splits C5 into C5a & C5b
- 10. C5b stays attached to C14b2b3b
- 11. C6, C7, C8 & C9 bind to C5b forming the MAC (membrane attack complex)
- MAC: C14b2b3b5b + C6, C7, C8, & C9
ORDER: 1, 4, 2, 3, 5, 6-9
Membrane Attack Complex (MAC)
- made up of C14b2b3b5b + late components C6-9
- triggered by C3b attaching to membrane surfaces & cleaving C5 → C5b sticks & the late components stick to IT
late component/part of the MAC protein that polymerizes to form pores in a pathogen's membrane through which fluid can rush, lysing the foreign cell
What are the most important ways complement defends against infectious organisms?
1. Opsonization: coating infected cells with Ig (most important opsonin) & C3b
enhances the ability of macrophages & neutrophils to phagocytose them
of cells toward injury & production of anaphylatoxins
: C3a & C5a
induce local & systemic inflammatory responses
3. C8 & C9 direct killing/lysis of organisms - punch holes in surface & lyse
Rates of Bacterial Digestion
- Neutrophils alone digest organisms slowly
- Rate of phagocytosis increases with Neutrophils + Antibody
- Phagocytosis is extremely efficient in the presence of neutrophils, antibody & C3b (complement)
- someone lacking complement can't kill bacteria quickly
C3a & C5a carry out what function of the complement system?
C3a & C5a carry out the chemotaxis function of the complement system, as well as the degranulation + anaphylatoxin production
C3a & C5a
- stimulate inflammation by:
- 1. attracting phagocytic cells (neutrophil polymorphs) chemotactically to the site of infection
- 2. stimulating the release of anaphylatoxin (eg. histamine, inflammatory chemicals) by degranulating basophils + mast cells
- inhibits the binding of C1 to the Fc region of an antibody bound to an antigen
- C1-INH is a protein in the blood that turns the whole system off; without it a person can have problems
Alternative Complement Pathway
- triggered by C3b binding directly to bacterial/viral products, especially lipopolysaccharide (LPS) aka endotoxin from the cell walls of gram- bacteria & some yeasts
- results in the opsonization of pathogens
Which parts of the alternative complement pathway are unique & which are also used by the classical complement pathway?
- UNIQUE: serum factors B & D + Properdin
- Shared: C3, C3a & C3b, C5 → C9
- there is no C1, 4, or 2 in the alternative complement pathway
- C3 is continuously being broken down into a & b; there's always a tiny amount of C3b in the blood
- if a foreign bacteria/virus gets in, C3b will attach to it, bind factor B & D & Properdin
- this newly generated polymer, C3bBbP, splits C3 normally & continues the complement cascade started @ the C3 step (bypassing C4)
Why must activation of the alternative complement pathway be tightly controlled?
because C3b is normally present in the circulation in small amounts as a result of spontaneous hydrolysis of C3 - it's always primed & ready to go
Factor H & Factor I
two inhibitory proteins that constantly inactivate C3b, inhibiting the alternative complement pathway
formed during activation of the alternative complement pathway after C3b has detected a foreign particle (eg. LPS) & complexed with/undergone a series of reactions involving factors B & D + Properdin
Lectin (Mannan Binding Ligand) Complement Pathway
- activated by organisms with mannose on their surface (eg. bacteria)
- initiated when the protein MBL (mannan-binding lectin) binds to carbohydrates on the surface of microbes
- MASP 1 & 2 are also important
- together all 3 activate the cleavage of C4 & C2 (classical complement pathway components) to form C4b2b then continue down the normal complement pathway
What proteins are important for the lectin complement pathway? (5)
- MBL (mannose binding lectin)
- MASP 1
- MASP 2
What kind of bacteria cannot activate the lectin complement pathway?
- gram positive
- they do NOT have mannose on their surface
The alternative & lectin complement pathways are part of which immune system?
- they are both effector arms of the INNATE immune system b/c they occur in the absence of antibody
- they show that a lack of antibody production doesn’t mean NO complement pathway
A deficiency in which complement protein would cause a more serious condition than missing a random or early protein in one of the 3 complement pathways?
- it functions in ALL 3 complement systems
SLE (systemic lupus erythematosus)
- can be caused by an absence of C1q, C2 or C4
- deficiency of these tend to cause autoimmunity due to an impaired ability to process & clear immune complexes
- bacterial infection is not an issue b/c the 2 nonclassical pathways can combat such immune disruptions
Absence of C1q, C2 or C4
- do NOT get recurrent infections, but they ARE prone to getting Lupus (SLE)
- eg. if you see a young boy with SLE, a rare condition in males, he may have a deficiency in C1q, C2, C4
What does absence of C3 cause?
- severe recurrent bacterial infectionsnone of the complement pathways can function
- treat by giving plasma instead of purified C3 to combat infections
- can't give purified C3 because individual may make an antibody to it because he/she’s never SEEN it before
What does absence of C5 cause?
- bacterial infections that are LESS severe than those seen in a C3 deficiency
- without C5a → can't punch holes in bacteria membranes or do as efficient chemotaxis
What can cause overwhelming Neisserial infections?
- an absence of later complement components → C6, C7 or C8 (FCs used to say C5b also)
- N. meningitidis & N. gonorrhea (gram-) cause an overwhelming infection because holes can't be punched in bacteria that are normally disposed of by complement when they enter blood stream by formation of transmembrane pores
- without C6, C7 or C8, bacteria can spread & infection may manifest in abnormal areas
- other overwhelming infections (not just neisserial) can occur (endocarditis, meningitis)
What processes are still functional when there's an absence of C6, C7, or C8 (aka when there's overwhelming Neisserial infection)?
- chemotaxis, anaphylaxis (C3a & C5a)
- opsonization (C3b)
- these processes all still function normally, which is why these people are mostly not immunocompromised
Generally, what does absence of alternative pathway components lead to?
recurrent bacterial infections
FCs also used to say that a deficiency of the alternative pathway component properdin, or of factors B or Dpyogenic = bacteria that cause pus
What causes infection predominantly in childhood?
absence of Lectin pathway proteins
Hereditary Angioedema (HAE)
- a rare autosomal dominant disorder caused by an inherited deficiency or dysfunction of the C1 inhibitor (C1-INH)
- C1 binding to Ig Fc is NOT inhibited
- there is uncontrolled cleavage of C2 & C4
- characterized by recurrent episodes of angioedema that most often affect the skin & the mucosal tissues of the upper respiratory & GI tracts
- these recurrent episodes of angioedema occur without urticaria or pruritus
What is a potentially dangerous complication of Hereditary Angioedema (HAE)/C1 deficiency or dysfunction?
- angiodema (swelling) is self-limiting, however laryngeal involvement may cause fatal asphyxiation
- patients with this deficiency do not have any issue combating infection
Control of the Immune Response
What can happen if a person's immune response fails to be turned down after an antigen has been destroyed?
What are some ways T cells are regulated to be turned down?
- 1. CTLA-4
- 2. PD-1
- 3. Fas/FasL
- 4. Tregs
- 5. Cytokine Mediated Regulation
- a protein receptor expressed constitutively on Tregs but only upregulated in conventional T cells after activation
- CTLA-4 competes with CD28 to bind to B7 on an APC surface
- unlike the CD28-B7 interaction, B7-CTLA-4 transmits a negative signal to the activated T cell, turning off the response
Programmed Death 1 (PD-1)
- an inhibitory receptor found on cytotoxic T-cells
- it interacts with PD-L1 found on tumor cells, PD-L2 found on dendritic cells, & macrophages → inhibiting immune responses
- PD1 is a receptor on CD8+ cells that turns OFF the CD8+ cell when complexed to ligands like PD-L1 or PD-L2
Pembrolizumab & Nivolumab
- anti PD-1 checkpoint inhibitors
- they turn the inhibitors OFF so T cells can keep functioning - are new immunotherapy drugs
- activated T cells develop FasL on their surface
- Fas is normally found on ALL T cells
- when they become activated they develop FasL which interacts with Fas, causing apoptosis of the T cell & death
- another mechanism by which T cells get turned down
- we are uncertain how cells know to express FasL
Tregs (T-Regulatory Cells)
- T reg cells make suppressor cytokines: IL-10 + TGFβ that inhibit T cells
- IL-10 is one of the cytokines made by APCs
- Treg cells might have CTLA-4 on their surface
What happens if you genetically engineer a mouse without Treg cells?
that mouse gets Autoimmune Disease
Cytokine Mediated Regulation
- IL-12 stimulates T cell differentiation into Th1 cells, which themselves secrete IFNγ
- IFNγ downregulates Th2 cell differentiation
- IL-4 stimulates T cell differentiation into Th2 cells, which themselves secrete IL-4
- IL-4 downregulates Th1 cell differentiation
the responses each INHIBIT other, & serve as another mechanism of immune response regulation
- lack of response to a specific antigen
- there is failure to induce immunity to a specific antigen
- (something a transplant surgeon dreams of)
- eg. how can a kidney be transferred with toleration: a circumstance in which we don’t want to immunosuppress the whole body, just want to immunosuppress to one antigen or group of antigens
Self (Central) Tolerance
- unresponsiveness to self antigens - we have this
- brought about in the thymus by negative selection
What happens to cells that escape Central (Self) Tolerance?
- dealt with my mechanisms of peripheral tolerance
- 1. clonal deletion
- 2. clonal anergy
Is Central Tolerance perfect?
- 20% of us have (low level) antibodies against our own DNA
- patients with Lupus have high levels of antibodies against their own DNA
- this is an example of when self tolerance breaks down, that negative selection isn’t 100%
- sometimes you need to produce tolerance in the periphery outside of the thymus → peripheral tolerance
- continuous exposure to self-antigens causes continuous stimulation of T cells leading to apoptosis of auto-reactive lymphocytes
- occurs by process of activation-induced cell death (Fas-FasL)
- when T cells are CONTINUOUSLY stimulated they turn themselves off (via CTLA4 + FasL)
- clone becomes unresponsive because of lack of costimulatory signals (especially B7-CD28)
- (B7: APC; CD28: T cell)
- if you transplant skin from a black mouse onto a white mouse IN UTERO the recipient won't reject the graft & will be born TOLERANT to black mouse antigens (can get organ transplants from both white & black mice)
- fetal tolerance lasts for a few days after birth
- eg. if baby is born with a severely defective heart, you can do a transplant immediately & it's possible rejection won't occur right away
Can adult tolerance be induced?
no - adult tolerance is very difficult to be induced
- immunological response against self antigens due to loss of self-tolerance
- there is a failure of negative selection in the thymus or a failure of immunological control mechanisms
- the fundamental problem is that there's an imbalance between immune activation & immune control
- eg. Lupus, ulcerative colitis, multiple sclerosis, Crohn's disease, Sjogren's disease, rheumatoid arthritis, psoriasis, scleroderma, autoimmune hemolytic anemia
What causes autoimmune disease?
- unknown, but there are 3 components to why this may happen
- 1. there are problems in immune regulation
- 2. genetics
- 3. various environmental factors which may give rise to AiDs (eg. smoking increases risk of rheumatoid arthritis)
What are some immunological factors that could cause autoimmunity?
- 1. exposure of hidden antigens (sympathetic ophthalmia)
- 2. polyclonal lymphocyte activation
- 3. defective T cell regulation:
- - defective Fas-FasL interactions: T cell has FasL, most cells have Fas
- - imbalance between CTLA-4 & CD28 (no CTLA-4 = overactive T cells)
- - defective Treg cells (CD4 & CD25)
How can hidden antigens cause autoimmunity?
- any tissue antigens normally hidden from circulation & not seen by the developing immune system won't be exposed to developing T cells & induce self-tolerance
- if these hidden antigens are later exposed to mature T cells an immune response will be generated
- this could occur after tissue destruction by infections or trauma or other means
- eg. autoantibodies to sperm after vasectomy or testicular trauma, antibodies to heart muscle after myocardial infarction, or antibodies to lens protein after eye damage (sympathetic ophthalmia)
- certain cells in the retina of the eye are NOT normally seen by the immune system
- if you damage those cells & antigens are released, you now may make an immune response against previously hidden antigens
- after injury to 1 eye, the other eye sometimes has to be removed because the body will make an immune response against retinal proteins in general
Polyclonal Lymphocyte Activation
- excessive or uncontrolled cytokine production may cause abnormal lymphocyte activation, including auto-reactive B & T cells
- could happen following preferential activation of TH1 cells (the main producers of IL-2)
- cytokines may produce tissue damage by upregulating adhesion molecules, or they may upregulate costimulatory molecules B7 & CD28 causing increased B cell activity
- EBV (viral) infection stimulates B cells non-specifically; might activate B cells against themselves
- Similarly super antigens stimulate T cells non specifically → may activate a T cell that is anti-self
What does a super antigen do?
- it attaches to the outside of a T cell receptor & to the MHC Class II molecule causing T-cell activation
- super antigens can cause cytokine storms
What are two examples of diseases caused by super antigens?
- 1. Staphylococcal food poisoning
- 2. Toxic Shock Syndrome
What happens if someone has defective CTLA-4?
defective CTLA-4 → uncontrolled activation of T cells
Genetic Factors in Autoimmunity
- AiDs are more common in family members (certain inbred strains of mice like New Zealand white & black are more succeptible to autoimmunity)
- there is ↑ incidence in twins
- there's an association between AiDs & MHC (HLA) types
HLA associated with Autoimmunity
- there are certain antigens present on foreign pathogenic organisms that are ALSO present within our bodies
- eg. rheumatic fever antigen looks similar to heart valve proteins
- the proliferation of anti-rheumatic fever antibodies targets the bacteria 1st & then damages the patients heart after a streptococcal infection (heart murmur)
What AiDs can be associated with Molecular Mimicry?
- 1. Rheumatic Fever: anti-strep Ig is made when fever isn't treated with penicillin; cross-reactive antibodies or T cells attack human heart muscle
- 2. Diabetes
- 3. Multiple Sclerosis
- people who present with Diabetes/MS will sometimes have had a recent previous illness
- something that stimulates & increases the immune response
- microbes can act as adjuvants
Is autoimmunity more common in females or males?
- AiDs are more common in women
- SLE is 9x more common in women than in men
- could potentially be due to female hormonal influences
What primarily mediates tissue damage in Autoimmunity?
- antibodies, T cells, or both humoral & cell mediated immunity
- auto-antibodies cause myasthenia gravis & autoimmune hemolytic anemia
- T cells cause Crohn's disease, insulin-dependent diabetes mellitus, psoriasis, multiple sclerosis
- humoral & CMI cause Hashimoto's thyroiditis or rheumatoid arthritis
Which AiDs are caused by activated T cell tissue destruction?
- 1. IDDM (insulin-dependent diabetes mellitus)
- 2. rheumatoid arthritis
- 3. multiple sclerosis
- 4. Crohn’s disease
- 5. Psoriasis
- 6. Celiac disease
- all of these diseases are primarily caused by T cell attack (which may be followed by auto-antibody production)
- from one person to the same person
- usually done with skin from one part of the body to another, i.e. in order to heal a burn: skin from thigh to wherever is damaged
- person to a genetically identical recipient
- rare occurrence: need to have identical HLA; usually happens between twins
- person to a genetically different recipient
- common: kidney, bone marrow, liver, heart
- graft to a different species
- pig → man
- worry about this is that you can pass animal viruses to human receiving the transplant
How do my body's T cells recognize a graft as foreign?
- 1. my APCs process & present the graft's (donor) MHC peptides to my T-cells [same way we always recognize foreign molecules]
- 2. my T-cells recognize unprocessed donor MHC molecules directly on graft APCs (our T cells can recognize donor HLA on APCs from the graft)
- #2 is the ONE exception to T cells only recognizing peptides in our OWN MHC molecules; unique aberration to know about
- happens within minutes or hours as a result of pre-formed antibodies in the recipient against the donor
- instigated by complement binding to pre-formed antibody & initiating powerful destruction of the tissue
Why might Hyperacute rejection of a transplanted organ occur?
- could occur due to antibodies having been previously made against HLAs/WBCs in transfusion blood that had previously occurred
- why blood banks filter blood & only give RBCs now
- coud also occur to a mother who's been exposed to her baby's cells during birth, leaving her resistant to her child's & her husband's HLA
- before transplant is done need to make sure recipient doesn't have an antibody against the donor
- happens after ~10-14 days as a result of mainly CMI but you also make some antibody to the foreign tissue
- the recipient's T cells reject the foreign HLA types
- takes 10-14 days because the graft antigen has to be presented to & activate T cells
- T cells make IL-2, proliferate, attack the graft, make cytokines, etc.
- there's a build up to the immune response
- can happen months or years after the transplant as a result of antibody, T-cell, & NK cell attack on the graft
- due mainly to antibody made against the graft → humoral immune response
- NK & T cells also attack the graft
- occurs after an extended period of immunosuppression
What is the mechanism by which a recipient's body Acutely Rejects an Allograft (person to a genetically different recipient)?
- direct contact between CD8+ cells & the graft
- CD8+ cells recognizes an MHC class I molecule on the graft's APC
- T cell's FasL binds to the APC's Fas → induces apoptosis
- T cell releases perforin & granzyme into the APC, killing it
- acute rejection takes 10-14 days to occur
What are other ways a recipient's body acutely rejects an allograft?
- 1. locally released cytokines & chemokines causing inflammation, macrophage activation & infiltration of phagocytic cells at graft
- 2. antibody may be made against donor HLA: induces destruction via complement (holes punched in cell membranes) or ADCC (Antibody Dependent Cell Cytotoxicity)
- 3. Natural Killer cells can directly attack & destroy graft cells
- acute rejection takes 10-14 days to occur
Antibody-Dependent Cellular Cytotoxicity (ADCC)
- 1. antibody binds antigens on the surface of target cells
- 2. Fc receptors on NK cell surface recognize bound antibody
- 3. cross-linking of Fc receptors signal NK cells to kill target cell
- 4. target cell dies → apoptosis
Stem Cell Transplantation
used with patients who have Cancer or lack some component of the immune response (eg. children with no B cells, DiGeorge Syndrome, or SCID)
When can we get stem cells for stem cell transplantation?
- 1. the peripheral blood (after treatment with colony stimulating factors)
- 2. umbilical cord blood
- 3. bone marrow
What is the major problem with bone marrow transplantation?
- competent T-cells from the donor may be transplanted giving rise to graft versus host disease
- aka donor T cells & APCs that were injected along with the stem cells start rejecting the recipient from inside because the host molecules' MHCs they detect are 'foreign' to them
- these donors proliferate & cause GVH disease
Graft versus Host Disease (GVH)
- a reaction of donor T cells against recipient MHC
- CD4+ T cells in the graft are activated by allogeneic [foreign] host molecules & produce a “cytokine storm”
- they recruit HOST/NATIVE T cells, macrophages, & NK cells to create the severe inflammation characteristic of GVH
What 3 conditions must be satisfied in order for GVH disease to occur?
- 1. the graft must contain live donor T cells (eg. bone marrow or thymus graft; no T cells on a kidney [washed])
- 2. recipient MUST be immunosuppressed - would be rejected immediately (hyper acute) upon transplantation if not; cancer patients/kids with immunodeficiency ARE immunosuppressed
- 3. donor and recipient must have DIFFERENT HLA types (can't happen in identical twins)
Cyclosporine A is fungal metabolite used to prevent graft/transplantation rejection. How does it accomplish this?
- it complexes with Calcineurin (a T cell phosphatase), INHIBITING T cell activation & preventing cytokine synthesis that activates effector cells to reject the foreign tissue → it IMMUNOSUPPRESSES
- FK506 (tacrolimus) is a drug that accomplishes the same thing
- calcineurin: phosphatase that ACTIVATES T cells
Besides cyclosporine & FK506, how else might one immunosuppress somebody receiving a graft transplant? (3)
- 1. corticosteroids: inhibit cytokine production & are anti-inflammatory
- 2. anti-CD3 monoclonal antibody: knocks out T cells, impossible for them to be activated, proliferate, & cause an immune response
- 3. anti-IL-2 receptor antibody
- interfering w/ any of this would cause immunosuppression
What is a problem with all forms of immunosuppressive therapy?
- normal immune responses against microorganisms are reduced → ↑ incidence of infection
- 1. intracellular bacteria (eg. mycobacterium tuberculosis)
- 2. large viruses (pox, herpes)
- 3. Fungi (Candida)
- 4. Intracellular Parasites (Toxoplasma)
- patients who’ve had transplants & die tend to die of infections like those above that REALLY require CD4+ cells
Why aren't all tumors perceived as foreign & killed?
while tumors DO have foreign antigens on their surface that can be recognized by the immune system, we don't know why they aren't they rejected
What are the types of antigens seen on the surface of tumor cells?
- 1. virally controlled antigens
- 2. oncofetal antigens
- 3. abnormal peptides made by tumor cells
- 4. mutant antigens (eg. Her2/neu)
- 5. tissue specific differentiation antigens
Viral Tumor Antigens
- viruses such as Hepatitus B & HPV cause cancer in that they instigate uncontrolled cell proliferation
- such cells present viral proteins in their MHC molecules on their surface
- Hepatitus B causes liver cancer & HPV causes cervical cancer
some antigens that are found on fetal but not adult cells are ALSO expressed by cancerous cells, such as alpha-fetoprotein on tumor cells of primary hepatocellular carcinoma (liver cancer) & carcino-embryonic antigen (CEA) on tumor cells of colon cancer
- an antigen found on the liver of fetuses but NOT in adults
- patients that develop primary liver cancer start making alpha-fetoprotein & all their cells express it
- condition: primary hepatocellular carcinoma
Carcino-Embryonic Antigen (CEA)
- an antigen found on the colon of fetuses but not in adults
- patients that develop colon cancer have CEA on their cell surfaces
- condition: colon carcinoma
- mutated (of normal proteins) peptide made by breast tumor cells
- if the tumor expresses Her2/neu, a monoclonal antibody called Herceptin can treat the cancer by binding to the surface peptide & killing cells that produce the mutated protein
- found in ~30% of cancers
Tissue Specific Differentiation Antigens
- different tissues make different proteins, & sometimes cancerous cells produce above average levels of certain proteins; can also simply test a tumor for what proteins are present & the findings can be used to determine what the disease is (markers)
- eg. PSA made by prostate cells, B-cells' CD19, CD20, & T-cell markers such as CD3, CD4 or CD8
prosate-specific antigen (PSA)
- made by prostate cells but made much MORE by prostate cancer cells
- as soon as you see the levels increase, it's like the person has prostate cancer
Normal B-lymphocytes have CD__, CD__, and _____ & ______ light chains in their antibodies. However B-cell lymphomas (malignancy of a single B-cell clone) have CD__, CD__, and ONLY _____ light chains in their antibodies.
- normal B-cell: CD19, CD20, kappa OR lambda light chains
- B-cell lymphomas: CD19, CD20, & ONLY kappa light chains
- lymphoma is a malignancy of a single B cell clone
What is an additional change on the surface of malignant cells involving MHC/HLA Class I molecules?
- tumor cells may lose HLA Class I
- this prevents such cells from interacting with CD8+ T cells → therefore CD8+ cells can't kill them
- NK cells that recognize & are cytotoxic to HLA Class I negative cells CAN kill them
Natural Killer Cells (NK cells)
- recognize & eliminate cancerous (malignant) or diseased (virally infected) cells that fail to exhibit class I MHC protein
- are large granular lymphocytes (LGL's)
- have Fc RECEPTORS that bind to IgG → ADCC
- can be activated by cytokines such as IL-2, 12, & IFN-γ
- can themselves produce cytokines (eg. TNFα, IFNγ, & IL-10)
What are the two ways an NK cell destroys tumor cells?
- 1. Direct Cytotoxicity: it recognizes that the cell lacks an MHC class I surface molecule, docks onto the cell, & pumps in perforin & granzyme to kill the cell
- 2. ADCC: if IgG antibodies are made to the tumor cell & bind, NK cell Fc receptors can bind IgG → using this connection to pump in & perforin & granzyme to kill the tumor cell
Immune mechanisms of tumor rejection: the main ways in which a healthy person kills any aberrant cancer
- #1 cytotoxic CD8+ T cells (CTLs) use granzyme + perforin, TNF, & expression of FasL (Fas is on the tumor)
- #2 activated macrophages
- #3 NK cells
How do tumors evade a host's immune system?
- 1. by releasing immunosuppressive factors like IL-10 & TGF-β
- 2. by releasing factors that activate Treg cells
- 3. by selecting antigen-negative variants: they change their antigens & become resistant to lymphocytes responsible for recognition (new & different T cells must be made specific to the tumor cells NEW adapted antigen)
How can we boost the immune response to get rid of cancer?
- 1. stimulate innate immune mechanisms (eg. imiquimod activates a TLR & BCG inflames the bladder wall)
- 2. Checkpoint inhibitor: block CTLA-4 or the PD-1/PD-1L interaction to remove 'brakes' from cytotoxic T cells
- 3. immunize against oncogenic viruses (eg. Hep B, HPV)
- 4. increase immunogenicity of tumors (try to make them stimulate more of an immune response; only experimental)
- 5. monoclonal antibodies (immunotoxins)
What disease are anti-PD-1 antibodies used to treat?
- PD-1 is found on tumor specific T cells
- PD-1L may be found on a tumor cell or APC
- when the 2 surface proteins interact, the T cell is turned OFF
- anti-PD-1 antibodies prevent the interaction so T cells can continue to proliferate & mount an immune response
What are the risks of blocking 'brake' mechanisms like CTLA-4 or PD-1?
- CTLA-4 → B7
- PD-1 → PD-1L
- blocking these interactions blocks mechanisms of self-tolerance
- this has the potential to cause autoimmunity, specifically inflammatory disorders (colitis, joint inflammation)
- severity of adverse effects has to be balanced against potential for treating serious cancers
- (less severe with anti-PD-1 antibody)
- a drug which increases the expression of toll like receptor 7 (TLR7)
- when applied to the skin causes massive inflammation & skin to slough off
- useful for skin cancer
- vaccine against TB in other countries but here used for bladder cancers because it causes inflammation in bladder wall
- the inflammation is significant enough that superficial bladder & cancer sloughs off
- monoclonal antibodies attached to toxins such as ricin or radioactive isotopes that are delivered specifically to the malignant cells to initiate direct killing
- Rituximab targets CD20 on B cell lymphomas
- Erbitux targets growth factor receptors in colon cancer
- Herceptin (anti Her2/Neu) blocks growth factor signaling on breast cancer cells