FUN2: 10:00-11:00 Scribe: Ashley Holladay

FUN2: 10:00-11:00 Scribe: Ashley Holladay

Thursday, October 30,2008 Proof: Teresa Kilborn

Dr. Bucy Immunology Page 5 of 5

Immunopathology II- Autoimmune Diseasese

I.  Introduction [S1]:

a.  Organizing idea- what kind of Ag is driving an immune response is key to understanding the overall tempo and characteristics of the response.

b.  The problem with autoimmune process is that it presumes that one knows that the Ag driving the response is an auto- Ag, but in general, we don’t know for sure what the Ag is.

c.  In many autoimmune diseases, the Ag that is driving the reaction is unknown. You know there is an inflammatory lesion that is causing damage. You cannot find an infection. There is no history of an environmental agent. The presumption is that it is an auto-Ag.

d.  Tolerance- the normal process by which the immune system fails to recognize self Ag.

e.  There is a fine line between an occult infection vs. an autoimmune lesion. Difference because in an occult infection the goal is to get rid of the infection. With an autoimmune response, not much prospect of getting rid of an Ag.

f.  QUESTION: What do you mean by an occult infection?

g.  ANSWER: Something that you suspect is there but you cannot demonstrate in a clean experimental way- a hidden infection.

i.  Good example- periodontal disease- chronic infection that cannot be gotten rid of because of because of mechanical problems, what kind of bacteria it is. The infection produces inflammatory changes and it is the inflammatory changes that do the large part of the pathologic damage of destroying gum tissue, eroding into bone, etc.

ii.  If you could get rid of the infection, that would solve the inflammatory lesion.

iii.  Treating the immune mechanisms to prevent the damage allows the infection to progress

iv.  There is a tradeoff interaction. This is not an infection that would get completely out of control and get septic, not an infection like the flu that would run away and kill you with no effective immune response.

v.  Dr. Jekyll/ Mr. Hyde example: You could suppress the inflammatory aspect but that causes problems. If you can’t get rid of the infection- problems as well.

II.  Organ Specificity[S2]

a.  Diseases that have immune components that are thought to be auto-Ag driven are usually separated into organ specific and non-organ specific.

b.  Organ specific- response driven by primarily a single Ag. That Ag is localized in a particular organ and the immune response is specific to that particular organ. This is like contact sensitivity- you get the lesion where you get contact with the material. If the Ag is localized in a particular tissue, then immune injury is localized in that tissue.

c.  Can have overlap. Vasculature- Ag present in endothelial cells. There are endothelial cells present all over the body. Here it can be a tissue type and not an organ of the traditional sense. If a tissue type is localized in many spots, it can be generalized in appearance and still be Ag- specific.

i.  Ex: synovial tissue/ joints. They are distributed around the body and think of that type of lesion as an organ specific process even thought the organ may not be localized.

d.  Non-organ specific autoimmune diseases- immune complex mediated processes. Immune complexes localize, not necessarily because of a specific Ag, but it tends to be systemic. (Skin, joints, kidneys)

i.  Kidney- glomerulus sensitive

ii.  Skin and joints- primarily anatomical reasons. Blood vessels in skin get cool and immune complexes precipitate preferentially when the temperature is lower. Blood going through the skin a little cooler and complex not quite soluble- precipitate more in skin as opposed to other organs where temperature warmer and different characteristics.

e.  [S3] Overview of how the immune system prevents reactivity to auto- Ag. There are several different levels.

f.  Auto-reactive cells (T or B cells) that are really specific for self Ag with high affinity get killed by during the development of those cells. If you delete those cells from the repertoire, then you have an absence of autoimmunity.

g.  Another tolerance mechanism: Cells can become anergic. By some experimental manipulation, demonstrate that the Ag specific cells are present but they don’t respond in the assay you choose to measure them by.

i.  Cell is there (not dead), but it doesn’t respond but generates lesions.

h.  Role of co-stimulatory molecules is major part of how cells may become anergic- stimulated with APC that are deficient.

i.  3rd mechanism: Immunologic ignorance- Ag is there and the reactive cells are there but they do not get together.

i.  Anatomical segregation or sequesteration- Lymphocytes (T cells) circulate throughout the body but not every Ag is exposed to APCs. If those Ags are released and allowed to be expressed by T cells it could lead to induction of an autoimmune response.

ii.  Keeping the Ag and the reactive lymphocyte away from each other is another mechanism of unresponsiveness.

j.  Some T cells directly recognize auto Ag but inhibit subsequent responses by other cells (supressors or regulators of the response).

III.  Breaking Tolerance [S4]

a.  Tolerance is the normal circumstance. If you break tolerance- autoimmune disease.

b.  Over a period of time, you don’t know what the mechanisms of tolerance are but do know what the autoimmune diseases are- so- you try to fit them together.

c.  If you conjugate self epitopes to immunogenic determinants you can get a response to those self epitopes.

i.  Immunize rats with thyroglobulin derived from a cow- rats got autoimmune thyroiditis. When they responded to the cow’s thyroglobulin, some cells helped respond to shared epitopes between the rat and the cow. Then those reactive lymphocytes caused an autoimmune disease in the thyroid.

d.  Anatomical localization with another strong response- adjuvants (Freund adjuvant)- mycobacterium mixed in a thick viscous oil- immunize with some auto Ag- generate a response to that auto Ag. If you just immunized with same Ag but not an adjuvant- you don’t get a response. The inflammatory milieu when you have one response going amplifies the “gains” of other autoreactive cells and allows them to slip the normal regulatory mechanisms that keeps them in check.

e.  Hidden self Ag- Sometimes trauma can induce autoimmune response.

i.  Sometimes if a male injures 1 testis, there is a barrier between the blood and seminiferous tubules where sperm develop. It releases materials from that spot and you can get an immune response where you would not usually have one because of the anatomic sequestration.

ii.  Both testes would become inflamed, not just the one that was injured. T Cells find that Ag out once they get activated and can cause an autoimmune lesion

f.  There are numerous genetic patterns of responsiveness related to the MHC. This area overall is growing with technical ability to sequence the genome and find subtle differences between individuals that are normally not overt diseases. But if you think of the immune system as very complex regulatory apparatus with feedback loops and gain knobs (some pathways more sensitivities, less responsive). If there is genetic difference in regulatory molecule in one of those pathways, they may be more sensitive to developing a disregulated response than someone who had that particular inhibitory mechanism tuned up. Another person might have more “jumpy” of a response

i.  There is a SNP (single nucleotide polymorphism) in the TNFα promoter that make people form TNF α at a lower level of stimulus than other individuals. Those people are more susceptible to developing some autoimmune diseases.

g.  [S5,S6] All of these things combined- There is a tissue injury or infection that induces activation of the immune system and the inflammatory milieu of local lesion and depending on genetic susceptibility, the presence of auto-reactive cells or the absence of a regulatory mechanism gives you a progressive type immune response and damage to whatever tissue this initial insult was localized to.

h.  There is some environmental insult- viral infection, drug hypersensitivity, trauma. Then in a subset of individuals, there is a malfunction in the normal regulatory pathway (genetic predisposition, not high penetrance effect, but susceptibility). You have to have the right environmental circumstances, a genetic predisposition and the development of progressive immune response.

i.  Once you get a progressive immune response, the disease depends largely on the tissue that is being attacked. Some tissues are resilient and you don’t lose function even if there is an intense immune response. Other types of tissues are delicate, and an immune response can deliver a knock-out blow.

j.  The way the disease works as a clinical entity has more to do with the target tissue.

k.  [S7]- This list is not to memorize.

i.  There is a whole family of diseases that are organ specific autoimmune diseases that are the same from an immunologic perspective

ii.  It is a T cell or Ab driven immune response against that tissue that results in destruction of that tissue and loss of function. Some of the diseases are reasonably common (juvenile diabetes) and many are quite rare.

iii.  Iatrogenic also listed here because a transplant has many of the same characteristics of autoimmune disease to interstitial Ag. T cells only know that they are supposed to respond to a particular Ag whether it is self, transplanted organ, or infection. All that matters is how much of that Ag is there and how long it takes to go away.

IV.  Autoimmune Diseases

a.  [S8] MS- relatively common autoimmune disease.

b.  Mechanism- immune mediated destruction (primarily CD4 T Cells and DTH type immune response) responsive to a protein in the oligodendrocytes of myelin tissues that make white matter that facilitates signal transduction in the axons.

c.  Histopathology- depends on the stage. Clinically you get a lesion that is separated in place (in the CNS where there is an attack) and in time (lose different function at different times).

i.  Ex: At one point your arm is numb. That gets better. Then you lose control of bladder. Then have weakness in leg, etc. It doesn’t follow a particular neuroanatomical system like other diseases. It skips around with respect to neuroanatomy.

ii.  It also comes and goes.

1.  Comes- local inflammatory lesion

2.  Goes- that lesion kills oligodendrocytes in a particular spot and you end up with a scar (multiple sclerosis)

iii.  [S9] Series of spinal cords of a person that died with MS- stained black color for myelin

1.  Lesions change in the different sections

2.  The multiple scars are present throughout CNS and show up as burned out kind of lesions in spinal cord

iv.  [S10] Higher power view- holes- where myelin has been destroyed and an immune response has killed off that set of tissue

v.  [S11] Scar=plaque- focus of T cells and macrophages infiltrating and killing in that spot

vi.  [S12] MRI- experimental MRIs done on MS patients over years.

1.  The pattern of these MRI images, the lesion would pop up, get bigger and go away. Then another lesion in a different area would pop up, get bigger and go away. These are independent. Some patients have a lot of new lesions per period of time. Other patients have a fairly low frequency. The number of times you see a lesion correlates with the disease progression rate. Some people become really debilitated. Others have a few episodes and then do well with little disease progression.

2.  To treat this you would like to decrease the disease progression.

3.  Within a lesion there is activation of T cells and macrophages, activated endothelial cells, recruitment of other cells, macrophages and neutrophils phagocytize and spill proteases and lipases into the extracellular tissue. Those enzymes degrade and digest bacteria and anything around- further injury. Further injury activates the immune response more and you get a cycle.

4.  Whatever Ag was driving that response gets cleared from that local area and you get left with a scar. That lesion scars down and you have a stable lesion. Problem- nervous transmission going through that region is less efficient. You are left with that deficit because the myelin doesn’t regenerate.

5.  We do not understand the mechanism that drives the reactivation of a lesion that is not previously inflamed. (Some think occult virus and infection that we can’t diagnose that is driving the progression. Most think it is a stochastic process- a certain probability of having a lesion- if the conditions are right- it is kind of random.)

6.  The number of lesions is much more frequent than the number of episodes of clinical activity (10:1).

d.  [S13] There is a similar condition in animals- EAE- experimental autoimmune encephalomelitis.

i.  The mechanism to generate this animal model is to mix the purified protein- myelin basic protein- with Freund’s adjuvant (oil and mycobacterium mixture) and immunize an animal (mouse). That animal will then get this paralytic hind limb paralytic disease with inflammation in the spinal cord.

ii.  You can take lymph node T cells and activate them in vitro to the myelin basic protein and activate it intravenously into a normal animal and without further manipulation, the animal will get hind limb paralysis and same pattern of tissue pathology of original animal. It doesn’t have anything to do with adjuvant or active immunization- just the presence of the activated T cells in the bloodstream is enough.