Mim Immunology Gu Part Ii

Front 1

Some self-reactive lymphocytes do mature & can be activated to cause autoimmune disease. Why do we let this happen?

Back 1

1. The determination of self-reactivity is indirect and, therefore, imperfect

2. Lymphocytes that have a degree of self-reactivity may also react with non-self antigens and contribute to immune defense

3. The immune system is permissive of self-reactive lymphocytes in order to maintain the broadest repertoire against infectious agents

Front 2

What are the different mechanisims of induction of autoimmune diseases?

Back 2

Molecular Mimicry – (Antigenic cross-reactivity)

Cryptic epitopes (Sercarz et al.)

Release of sequestered antigens

Hapten-Carrier Relationships

Inappropriate Expression of Class II MHC

Polyclonal B & T cell Activation –Mitogens/Superantigens

Chronic inflammation

Front 3

What happen when foreign antigen is so closely related to self epitope and interacts with self by accident?

Back 3

ANTIGENIC CROSS REACTIVITY
(molecular mimicry or the failure of molecular mimicry)

Infections can lead to autoimmune disease as a result of cross-reactive antibodies or T cells.

Could be considered to be an***hetical since pathogens attempt to go unnoticed by the immune system by making themselves look like their hosts.

Front 4

Which tissues in the body are immunologically privileged? Why is this important?


Bonus- how would tissue transplants react at these sites?

Back 4

Extracellular fluid from these sites does not pass through conventional lymphatics.

These sites are surrounded by tissue barriers that exclude naïve lymphocytes.

Antigens leaving these sites are accompanied by anti-inflammatory cytokines such as TGF-β.

These sites express Fas ligand and induce apoptosis of Fas-bearing effector lymphocytes.


Tissue grafts placed in these sites often LAST INDEFINITELY, and antigens placed in these sites do not elicit destructive immune responses.

Front 5

Why is it so bad to have a chronic infection? How would an ongoing infection affect the lymphocytes that bind self-antigen with low affinity?

Back 5

Toll-like receptors (TLR) occasionally mistake eukaryotic DNA


"The receptor TLR-9 promotes the activation of B cells specific for DNA, a common autoantibody in the autoimmune disease systemic lupus erythematosus (SLE). Although B cells with strong affinity for DNA are eliminated in the bone marrow, some DNA-specific B cells with lower affinity escape and persist in the periphery but are not normally activated. Under some conditions and in genetically susceptible individuals, the concentration of DNA may increase, leading to the ligation of enough B-cell receptors to initiate activation of these B cells."

Front 6

Why is T reg so helpful? How are they made in the thymus (natural)? How are they made in the periphery (induced) what do they do?

THE $$ QUESTION: How come the mucosa of the stomach don't FREAK OUT and attack commensal (good) bacteria in the gut??

What cytokines does it secret???

Back 6

In thymus- if they are specific for self antigen they become natural Treg cells.

In periphery, T- cells specific for self (or good bacteria) in presence of TGF-B become induced Treg.

So when the APC shows the self- antigen (or commensal bacteria) from the GI, T-reg says "calm the f*ck down everybody..." by secreting IL-10 and TGF-B.

Front 7

What are some ORGAN-SPECIFIC autoimmune diseases? What are some examples of SYSTEMIC autoimmune diseases?

Which dieseases can occur in clusters?

Back 7

Pancreas, kidney, Neuromuscular junction, thyroid are some organ specific diseases.

Front 8

What sort of autoimmune reaction do we see for MYASTHENIA GRAVIS?

Hint- occurs at neuromuscular junction... what sort of neurotransmitters do they use?

Back 8

Production of antibodies against acetylecholine (the α subunit) at neuromuscular jxn.

These autoantibodies bind to the receptor without activating it and also cause receptor internalization and degradation

As the number of receptors on the muscle is decreased, the muscle becomes less responsive to acetylcholine.

Less muscle contraction. :(

Front 9

What sort of immune reaction do we see in GRAVE'S DISEASE?

What autoantibodies are created against what??

We just learned this in MNE!

Back 9

autoantibodies specific for thyroid stimulating hormone. Accidentally turn on TSH membrane receptor. Stimulates thyroid hormone production--> HYPERTHYROIDISIM

Front 10

What are the four types of immune tissue injury reactions that are recognized?

Describe their
1.immune reactant
2. antigen
3. effector mechanism
4. example of hypersensitivity rxn

Back 10

GELL & COOMBS hypersensitivity rxn
aka ALLERGIC REACTIONS

type 1- IgE- mast cells
type 2- IgG- complement/ altered signalling
type 3- IgG- complement
type 4- Th1, Th2, or Cd8+ (activate macrophages, IgE- esionophils, or cytotoxic Tcells)

Front 11

What do all IgE immune reactions have in common? What specifically can cause the symptoms experienced by the patient to be so different from the same antigen?

Back 11

All IgE-mediated responses involve MAST CELL DEGRANULATION, but the symptoms experienced by the patient can be very different depending on ROUTE OF ENTRY

for example, on whether the allergen is injected directly into the bloodstream, is eaten, or comes into contact with the mucosa of the respiratory tract.

Front 12

Which type of antibody (including subclass) can cross the placenta barrier most easily?

When would this be a really BAD thing to happen???

Back 12

IgG 1 and IgG 3 can cross the easiest.

Front 13

What are the (7) different ways to induce an AUTOIMMUNE diesease?

Back 13

1. Molecular Mimicary
2. Cryptic epitopes
3. release of SEQUESTERED ANTIGENS
4. Haptin-Carrier relationships
5. Inapproriate expression of Class II MHC
6. Polyclonal B & T cell activation (Mitogens+ SUPERANTIGENS)
7. Chronic Inflammtion

**Pathology results from Type 2,3,4 allergy mechanisims

Front 14

What is the relationship between infection and autoimmunity? What is the most important step?

Back 14

Why? Because many episodes of pro-inflammatory cytokines have APC very active and signaling at high levels.

Front 15

What are pathogenic infections/ protective infections? How can this help or hurt for an autoimmune diease

Back 15

Certain infections can be protective of certain immune types.

Front 16

What do you call it when forgein antigen is so closley related to self-epitope that the immune system beings to interact with itself by accident?

Name a few examples of this disease

Back 16

MOLECULAR MIMICARY/ ANTIGENIC CROSS REACTIVITY

Infections can lead to autoimmune disease as a result of cross-reactive antibodies or T cells.

Could be considered to be antithetical since pathogens attempt to go unnoticed by the immune system by making themselves look like their hosts.

GUILLAIN- BARRE SYNDROME-- A PERIPHERAL NEUROPATHY FOLLOWING INFECTION WITH Campylobacter jejuni

The immune attack consists of deposition of IgM, IgA, IgG1 & IgG3 antibodies and complement on the axon & Schwann cell surface & infiltration of the nerve with macrophages & T cells
The antibodies react with gangliosides GM1, GM1b, GD1a & Gal-NAc-GD1a
T cells are CD4+, CD8+, and express αβ or γδ TCR

The most frequent cause of acute paralysis in the western world [incidence 1-2 per 100,000 per year]

Front 17

What sorts of conditions may lead to presentation of CRYPTIC EPITOPES that have escaped tolerance?

Back 17

T cells against dominant self-epitopes are rendered tolerant

T cells against cryptic self-epitopes escape tolerance

Under normal physiological conditions cryptic epitopes of a native antigen are inefficiently processed & presented. Thus, no threat of induction of an anti-self response.

Under inflammatory or other immunostimulatory conditions up-regulation of antigen processing may lead to presentation of a cryptic epitope by an APC

How? Increased uptake of antigen, up-regulation of MHC molecules, enhanced proteolysis of antigen, influence of cytokines, up-regulation of co-stimulatory molecules, modulation of peptide loading by HLA-DM

Front 18

What kind of hypersensitivity reactions are HAPTEN-CARRIER RELATIONSHIPS?

Back 18

Type 2 hypersensitivity

(Drug induced autoimmunity)

i.e penicillin, hydralazine

Front 19

What the hell is a hapten anyway? What does it do?

Back 19

HAPTEN is a small molecule that can elicit an immune response ONLY when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself. (In general, only large molecules, infectious agents, or insoluble foreign matter can elicit an immune response in the body.)

Front 20

What would be an example of inappropriate MHC class expression? Why is this bad?

Back 20

In autoimmunity- cells other than APC may express MHC II (and higher levels of MHC 1 all around)

(ex. B cells in pancreas for dibetus, thyroid acinar cells in Grave's Disease)

Front 21

What are the SUPERVILLANS of the autoimmune system? What can turn on T-cell regardless of peptide binding in the groove?

Back 21

MITOGENS & SUPERANTIGENS cause POLYCLONAL B CELL ACTIVATION.


LPS= lipopolysacharide

Front 22

What positive feedback cycle was Dr. Cole describing when he talked about "how you can never really clear the self-antigen... Once the wheels set in motion, it is never going to stop"

Back 22

CHRONIC INFLAMMATION.
- Positive feedback from inflammation
-inability to clear self-antigen
-broadening of immune response

Front 23

This is a really tough one:: How does one autoreactive T cell activate other auto reactive T+ B cells?

What is an example of this disease? What do they produce autoantibodies against? How does this happen?

WHAT TYPE OF HYPERSENSITIVITY RXN IS THIS?

Back 23

In SYSTEMIC LUPUS ERYTHEMATOUS (SLE) we have EPITOPE SPREADING

(Type III hypersensitivity- immune complex disease)

Basically, one T-cell can service many masters.

Best explination as of right now is DIFFERENT autoreactive B cells can be activated by a SINGLE CLONE of autoreactive T-cells specific for just one of the peptides of a protien in the COMPLEX.

(i.e. SLE usually produce autoantibodies against both DNA, histones, and other parts of complex.)

"...a B cell binding to any component of the complex through its surface immunoglobulin can internalize the whole complex, degrade it, and return peptides derived from the histone proteins to the cell surface bound to MHC (class II) molecules, where they stimulate helper T cells. These, in turn, activate the B cells.

Thus, a T cell specific for the H1 histone protein of the nucleosome can activate both a B cell specific for H1 (upper panels) and a B cell specific for double-stranded DNA (lower panels). T cells of additional epitope specificities can also become recruited into the response in this way by antigen-presenting B cells bearing a variety of nucleosome-derived peptide:MHC complexes on their surface."

Front 24

How do you deliver signal 1 AND signal 2 (You need both!) with the helper T-cell? What about in the absence of a T-cell?

Back 24

In THYMUS DEPENDENT activation, the interaction between CD40 LIGAND (CD40L, also called CD154) on the T cell and CD40 on the B cell contributes an essential part of this second signal.

For THYMUS INDEPENDENT antigens, a second signal can be delivered along with the antigen itself, through TOLL-LIKE RECEPTORS that recognize antigenassociated TLR ligands, such as bacterial lipopolysaccharide (LPS) or bacterial DNA (bottom panel).

Front 25

Why did Dr. Cole call the plasma cells "antibody machines"?

Compare and contrast between a resting B cell and a plasma cell the:
1. surface antibody
2. expression of surface MHC class II
3. rate of Ig secretion

Back 25

Resting naive B cells have membranebound immunoglobulin (usually IgM and IgD) and MHC class II molecules on their surface. Although their V genes do not carry somatic mutations, B cells can take up antigen and present it to helper T cells. The T cells in return induce the B cells to proliferate and to undergo isotype switching and somatic hypermutation, but B cells do not secrete significant amounts of antibody during this period. Plasmablasts have an intermediate phenotype. They secrete antibody but retain substantial surface immunoglobulin and MHC class II molecules and so can continue to take up and present antigen to T cells. Plasmablasts early in the immune response and those activated by T-independent antigens have usually not undergone somatic hypermutation and class switching, and therefore secrete IgM. Plasma cells are terminally differentiated plasmablasts that secrete antibodies. They can no longer interact with helper T cells because they have very low levels of surface immunoglobulin and lack MHC class II molecules. Early in the immune response they differentiate from unswitched plasmablasts and secrete IgM; later in the response they derive from plasmablasts that have undergone class switching and somatic hypermutation. Plasma cells have lost the ability to change the class of their antibody or undergo further somatic hypermutation.

Front 26

Which cytokines can induce an isotype switch?

Back 26

Front 27

On the genetic level, how does isotype class switching of heavy chain genes work?

Back 27

Resting naive B cells transcribe the genes for the heavychain isotypes μ and δ at a low rate, giving rise to surface IgM and IgD (first row). Bacterial lipopolysaccharide (LPS), which can activate B cells independently of antigen, induces IgM secretion (second row). In the presence of IL-4, however, transcripts of Cγ1 and Cε are initiated at a low rate from promoters that are located at the 5' end of each switch region (third row). These do not code for a protein but drive switching to IgG1 or IgE, respectively (see Section 5-19). Similarly, TGF-β gives rise to Cγ2β and Cα transcripts and drives switching to IgG2b or IgA (fourth row). It is not known what determines which of the two transcriptionally activated heavychain C genes undergoes switching in a given event. Red arrows indicate transcription. The figure shows class switching in the mouse.

Front 28

What are the specific and non-specific methods we can use to surpress the immune system in an organ transplant? (6 ways)

Back 28

1. ANTI INFLAMMITORY AGENTS
2. INHIBIT MITOSIS (CELLS DIVISION)
3. INTERFERE WITH IMMUNE CELL ACTIVATION
3. T/B CELL DEPLETION
4. BLOCK T CELL SIGNALS
6. REMOVE ANTIBODY

Front 29

What are some of the obvious and not so obvious draw backs of using these immunosurpressive drugs? (5 things)

Back 29

1. Toxic effects of agent
2. Infection / malignancies due to failure of immune surveillance
3. Failure in immune reconstitution (hpc)
4. Patient compliance / cost
5. Graft failure causes sensitization reducing success of second transplant

Front 30

During transplantation, how do we prevent immune responses that might destroy the graft or harm the patient?

Back 30

1.) MATCH histocompatibility molecules
2.) MONITOR/reduce SENSITIZATION
3.) SUPRESS immune RESPONSE
4.) Use LESS IMMUNOGENIC TISSUE
5.) Induce SPECIFIC TOLERANCE

Front 31

What do you call it when the graft attacks the recipient? What about when the recipient attacks the graft?

Which is more common in solid organ transplants?

Back 31

REJECTION- recipient immune cell mediated-
recp--->graft
(hyperacute/acute/chronic)
**solid organ primarily

GRAFT VS. HOST DISEASE (GvHD)-
graft--->recp.
(acute/chronic)

Front 32

What does the immune system see as foreign between graft donor and recipient? What are the alloantigens? (3 items)

Back 32

1. Blood group antigens - ABO
2. Major histocompatibility molecules
3. Minor histocompatibility molecules - other polymorphic proteins

Front 33

What is the difference between a HYPERACUTE rejection and an ACCELERATED ACUTE rejection?

Back 33

HYPERACUTE-
*Pre-exisiting SERUM ANTIBODY specific for graft
*COMPLEMENT mediated
*Within 24 HOURS post-transplant, often immediately with vascularized grafts
*Infiltration of neutrophils into grafted tissue leading to inflammatory reaction
*Blood clots within capillaries

ACCELERATED ACUTE REJECTION:
*Activation of MEMORY LYMPHOCYTES
*Memory B cells secrete antibody specific for graft
*Memory T cells
*Lymphocyte infiltrate
*Complement C4d deposition in tissues
*IN FIRST WEEK

Front 34

Which type of transplant (blood, HPC/bone marrow, solid organ, or immunologically privileged site):
1. Requires PRECISE HLA matching?
2. Relies more extensive on IMMUNE SUPPRESSION than HLA matching?
3. which sites are the easiest to transplant?
4. Requires separation of components used for transfusion?

Back 34

1. Hemopoetic Stem Cell (HPC)
2. SOLID ORGANS
3. Immunologically privileged sites
4. Blood transfusions

Front 35

Which type of immunity is the complement pathway? (innate or adaptive)

What are the different possible complement pathways?

What is the final step of the complement system?

Back 35

1. Complement is part of BOTH INNATE and ADAPTIVE immunity
2. Classical, Mannose Binding Lechtin, Alternative pathway
3. Final step is formation of MAC

Front 36

What are the fucntions of the COMPLEMENT PATHWAYS? (5 fxns)

Which step in the pathway do they all have in common??

Back 36

Functions of complement:
1. Chemotaxis (recruiting imflammitory cells)
2. Opsonization
3. Killing
4. Immune complex removal
5. B AND T-cell activation

THEY CONVERGE AT THE C3 CONVERTASE AND FROM THERE TO TERMINATION= SINGLE COMMON PATHWAY

Front 37

What things do the different pathways of complement bind to initiate C3 convertase?

Why is the classical complement pathway considered part of 'acquired immunity'?

Back 37

CLASSICAL PATHWAY- initiated by the binding of IgM or IgG to the pathogen surface. The change in conformation of the bound antibody exposes the site for C1 binding. Once bound C1 becomes catalytically active. Initially it was thought that the classical pathway could only be activated by IgM or IgG antibody but it is now clear that C-REACTIVE PROTIEN CAN BING C1q as can some bacterial surfaces.

**MANNOSE-BINDING LECTIN-- is a soluble PRR that can bind to specific arrays of MANNOSE and FUCNOSE on pathogen surfaces. Similar to C1, the change in conformation of the bound MBL renders it catalytically active.

**ALTERNATIVE PATHWAY is activated by the spontaneous hydrolysis of C3, called ‘C3 tickover’. If the exposed, labile thioester bond can immediately bind to a pathogen surface the pathway is activated. If not C3b decays.

Front 38

What classes of antibody activate complement and WHY?

Complement doesn't function at mucosal surfaces. Why not?

Back 38

Classic Complement activating:
IgM, IgG(1*,2,3)

Non-complement activating:
IgA(1+2), IgE

Don't want to damage barrier epithelia.

Front 39

Why do we need complement? What can complement do that antibodies can't do?

Back 39

Antibodies have NO INTRINSIC KILLING ACTIVITY.

Front 40

What is the biggest difference between IgM trying to activate compliment, and IgG trying to activate complement?

Hint-- think about the shapes of the antibodies...
BONUS?** Why don't IgG and IgM activate complement when soluble in the blood?

Back 40

only a SINGLE IgM molecule needed to activate complement

need at least TWO IgG molecules (density dependent) to activate pathway

In solution IgM is planar. In this conformation the complement binding site on the Fc region is masked and IgM cannot fix complement. This is a safety mechanism to prevent unwanted complement activation by immunoglobulins in solution. When IgM binds to the pathogen surface its assumes a crab-like conformation that exposes the complement binding site on the CH3 domain of the Fc region. Similarly when IgG binds to pathogen surfaces a C1q binding site is exposed on the CH2 domain of the Fc region. Note that a single molecule of IgM is sufficient to activate complement, whereas a minimum of two IgG molecules is required. The two molecules of IgG must be sufficiently close one to another to be bridged by the globular heads of C1q.

Front 41

What does this magical assembly of C3 CONVERTASE do in the complement pathway?

Hint-- (C3a,C4a,C5a)
(C3b)
(C5b,C6-9)
all these groups play a special role.

Back 41

C3 convertase generates

(1) ANAPHYLATOXINS (chemotactic factors) C3a, C5a and C4a. C3a and C5a are the most potent and are termed
(2) a powerful OPSONIN, C3b, that aids in phagocytosis and
(3) begins the terminal events of the cascade leading to the formation of the MEMBRANE ATTACK COMPLEX (C5b-C9) that creates pores in the pathogen envelope resulting in osmotic lysis.

Front 42

The MANNOSE BINDING LECTIN PATHWAY and CLASSIC COMPLEMENT PATHWAY are basically the same exact thing! What is the ONLY thing that is different?

Back 42

mannose-binding lectin pathway is initiated by the mannose-binding lectin and not C1 (Classic)!


Beyond this the two pathways are identical.
They both are heterotrimers that look like a bunch of daffodils.

Front 43

What are the two amplification steps in the CLASSICAL complement cascade? Which molecules bound together make the C3 convertase? Which make up the C5 convertase?

Back 43

C3 convertase= C2b+ C4b

C5 conertase= C2b+C4b+C3b

or C4b2b and C4b2b3b

Front 44

How is C3 conertase made in the ALTERNATIVE PATHWAY? What additional complement is needed to stabilize this funky convertase?

Back 44

Spontaneously activated by pathogen surfaces.

Hydrolysis of C3.

PROPERDIN

Front 45

What are the two different type of C3 convertase? What about the C5 convertase?

Back 45

For C3 convertase
Classic/ MBLP: C4b2b
Alternate: C3bBb

C5 convertase---
Classic/ MBLP: C4b2b3b
Alternate: C3b(2)Bb

Front 46

What is the most powerful opsonin of the complement cascade?

Hint- can be made via innate or adaptive immunity

Back 46

C3b= powerful complement opsonin

DON'T FORGET-- it needs C5a to work!!

Front 47

All this bullshi*... c3b, iC3b, C3dg C3d... blah blah blah.... What are their roles? how do they work? Which cells do they affect? Which one plays an important role in phagocytosis?

WHICH CELLS HAVE C3b ON THEM?!?!?!? WHY IS C3b significant??

Back 47

C3b receptors play an important role in PHAGOCYTOSIS (powerful opsonin!!)

iC3b is a proteolytically inactive product of the complement cleavage fragment C3b that still opsonizes microbes, but cannot associate with Factor B, thus, preventing amplification of the complement cascade or activation through the alternative pathway.

C3d plays a role in enhancing B cell responses.

C3dg is a breakdown product of C3b. C3b is broken down progressively to first iC3b, then C3c + C3dg, and then finally C3d.

Front 48

So we know IgG an C3b are both powerful opsonins... What happens when IgG and C3b combine superpowers?!

Back 48

SYNERGISTIC OPSONIZATION

Front 49

What are ANAPHYLATOXINS?

Back 49

fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system. they cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability.They also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals.

Anaphylatoxins are able to trigger degranulation (release of substances) of endothelial cells, mast cells or phagocytes, which produce a local inflammatory response. If the degranulation is widespread, it can cause a shock-like syndrome similar to that of an allergic reaction.