Type II Imunopathology

Question 1

NIH recognizes

Answer 1

80 conditions of autoimmunity (but there are more). 5-8 per 100 in US have one or more of these.

Question 2

immunopathology depends on 3 factors

Answer 2

genetics, environment and bad luck

Question 3

5 pathological processes in all these conditions

Answer 3

they are must MECHANISMS, most actual disease have been found to involve more than one mechanism.

Question 4

The mechanisms: Type I

Answer 4

Symptoms or pathology due to IgE antibody. Since the type of B-cell-helper Tfh cell that drives switching to IgE seems to be closely related to the Th2 cell, Th2-mediated events are often seen along with those caused by IgE.

Question 5

The mechanisms: Type II

Answer 5

Pathology due to IgG, IgM, or IgA antibody causing harm to self. In most cases this refers to autoantibodies. Type V was separate; but it is now folded into Type II, as it involves autoreactive antibody against surface receptors which happen to stimulate (rather than damage) the cell.

Question 6

The mechanisms: Type III

Answer 6

Pathology caused by the formation of immune complexes which are trapped in the basement membranes of blood vessels and activate complement, leading to vasculitic inflammation.

Question 7

The mechanisms: Type IV

Answer 7

Pathologic outcomes of normal or abnormal (including autoimmune) T cell responses, including both helper and cytotoxic cells.

Question 8

Chronic Frustrated Immune Responses.

Answer 8

It refers to conditions in which the body is using the adaptive immune response to try to get rid of antigens that it never can. These include things like normal gut flora (as in Crohn disease), skin flora (psoriasis), chemicals (as in chronic beryllium disease), or foods (gluten in celiac disease). The ANTIGEN can be neither disposed of nor effectively walled off.

Question 9

Type II discussion

Answer 9

TYPE II. This form of immunopathology is due to the actions of antibodies directed against a specific target tissue, cell, or molecule; so it is one of the forms of AUTOIMMUNITY. There is also T cell-mediated autoimmunity, which is a part of Type IV immunopathology. Note that it’s technically a lot easier to detect specific autoantibodies than autoreactive T cells.

Question 10

Complement-mediated damage.

Answer 10

Tissues against which antibodies are made can be damaged by lysis (red cells in autoimmune hemolytic anemia), by phagocytosis (platelets in autoimmune thrombocytopenic purpura) or by release of the phagocytes’ lysosomal enzymes and reactive oxygen species (probable in myasthenia gravis and Goodpasture disease). Also platelets can be opsomized and taken out.

Question 11

Stimulatory Hypersensitivity

Answer 11

If the autoantibody happens to be directed against a cell- surface receptor, it may behave as an agonist, mimicking whatever hormone or factor normally works at that receptor. ►The classic example of this is the ‘long-acting thyroid stimulator’ found in the blood of most patients with hyperthyroidism. LATS, as it was called for a long time, is simply an IgG antibody to the TSH (thyroid-stimulating hormone) receptor on thyroid cells

Question 12

Inappropriate tachycardia

Answer 12

a fast heart rate without cardiac abnormalities. About half have been shown to have autoantibodies to the β-adrenergic receptor, which are stimulatory, like epinephrine; the effect can be REVERSED by the beta blocker propranolol. Often seen in young women.

Question 13

Myasthenia Gravis

Answer 13

Disease of progressive muscle WEAKNESS, because patients are making antibody to the acetylcholine receptor (AChR). ►The antibody to the alpha subunit of the AChR does the real damage, which is complement- and neutrophil-mediated. Neutrophil “burps” out bad stuff on the end of the receptors and then the AChRs get harder and harder to stimulate. SIGN - drooping eyelid is an early sign. TREATMENT: drugs that can increase duration of achtylcoline duration.

Question 14

Rheumatic Heart Disease

Answer 14

Defined as heart disease occurring shortly after a streptococcal infection, for example a ‘strep throat.’ ►There is very good evidence that it is due to CROSS-REACTION between a Group A Streptococcus M-protein antigen and a structure on the heart’s endothelial lining, probably laminin on heart valves, followed by neutrophil-mediated tissue destruction. Often seen in kids since there immune system is not developed enough.

Question 15

Rheumatic fever

Answer 15

is the same disease as Rheumatic Heart Disease with more widespread manifestations, including in the skin and CNS.

Question 16

Dressler Syndrome

Answer 16

Most people who have a heart attack will make some AUTOANTIBODY which reacts with heart. This seems to do them no harm. Dressler syndrome manifests as persistent cardiac pain, fever, malaise, and pericardial effusion seen after heart attack (and more commonly after heart surgery) which is directly related to an immune response to pericardial or myocardial antigens. A better name might be post-cardiac injury syndrome. Treated with anti- inflammatory agents, it usually gets better as the heart heals. Referred to as sequestered.

Question 17

GOODPASTURE SYNDROME

Answer 17

involves formation of ►autoantibodies to
lung and kidney basement membranes (BM) (which are the collagenous non-living connective tissue framework upon which the endothelial cells of capillaries sit). ►There is an antigen (Type IV collagen)sharedbetween the BM’s of these two organs, because other organs are not involved. The patients have persistent glomerulonephritis, and
pneumonitis with pulmonary hemorrhages (see coughing blood). In GOODPASTURE the antibody is directed against the basement membrane, not trapped as clumps, so the staining by immunofluorescence is sharp and ‘linear,’ not ‘lumpy-bumpy’ as it is in Type III, immune complex conditions.

Question 18

AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ATP)

Answer 18

These patients have bleeding abnormalities due to destruction of platelets (thrombocytes) by autoantibody;; ►the platelets are opsonized and their destruction, mainly in the spleen, is rapid.

Question 19

AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

Answer 19

Like ATP, this may follow a viral infection, or be associated with another autoimmune syndrome, or cancer. ►Many drugs, such as penicillin, methyldopa, chlorpromazine and quinidine, can induce AIHA, usually temporarily. In the rare condition paroxysmal cold hemoglobinuria (PCH), the patient experiences hemolysis after exposure to cold.

Question 20

Systemic lupus erythematosus (SLE)

Answer 20

This is the classical multifactorial autoimmune disease, with both genetic and environmental causes and triggers;; but we still don’t understand it. Everything is going wrong. Many think it could be a disorder of the management of apoptotic cells. people with lupus may make antibody to: nuclear and nucleolar proteins; DNA; RNA; erythrocytes; clotting factors; platelets; skin; and T cells. ►MOST SEVERE SLE is where Antibody to double-stranded DNA is pathogenic, and may explain not just the kidney disease but also the characteristic facial butterfly rash, with local immune complex formation near sun-damaged, DNA-releasing skin cells. NOTE that antibody cannot get through cell membrane, so the interaction is will DNA in the blood, it makes complexes with antibody and then goes to the kidney and get lumpy bumby. TYPE III problem. Butterfly skin on nose is bc that is think skin and gets easily sun damaged.

Question 21

Rheumatoid arthritis

Answer 21

It is the ‘inflammatory arthritis.’ RA affects women more than men, and usually attacks the smaller joints, especially those of the fingers, first. The initial evidence that it was autoimmune came with the discovery of rheumatoid factor (RF)(a rare antibody) which can be detected by adding the patient’s serum to microscopic beads that are coated with normal human IgG. RF makes the beads agglutinate; ►it is IgM, but it isanti-IgG! RA respond extremely well to rituximab, a monoclonal antibody against the CD20 on the surface of B cells, which effectively depletes them from the body.

Question 22

HASHIMOTO THYROIDITIS.

Answer 22

An inflammatory disease of the thyroid in which there is very good evidence for both T and B cell immunity to various thyroid antigens, including thyroglobulin. The antibodies to thyroid antigens are destructive, not stimulatory. Histologically the thyroid is infiltrated by T cells. It may be that T cell damage allows antibodies access to normally sequestered antigens, which worsens the condition. The result is hypothyroidism.

Question 23

Other diseases

Answer 23

There are often autoantibodies found in conditions that are known to be T cell-mediated; this indicated that immunity may be generally dysregulated. In celiac disease, there is an antibody to tissue transglutaminase that is very useful for diagnosis, and in Type 1 (childhood) diabetes several antibodies to islet-associated antigens are seen which provide prognostic information; but in neither of these conditions are they thought to be pathogenic,

Question 24

Foreign + self hybrid

antigen

Answer 24

REREAD BOTTOM OF PAGE 6!!!!!

Question 25

Forbidden clone

Answer 25

Foreign + self hybrid

antigen

Question 26

Cross-reaction

Answer 26

between a foreign antigen and a self antigen. By the time the patient develops clinical symptoms, the triggering antigen may be long gone, with the process being maintained by autoimmune responses to normally-sequestered antigens released from damaged cells.

Question 27

Passive antibody

Answer 27

In a child with hemolytic disease of the newborn (see Immunohematology); in a patient getting a mismatched transfusion; in a child of a mother with myasthenia gravis or SLE.

Question 28

Innocent bystander

Answer 28

A common mechanism, in which there is damage to normal tissue which happens to be associated with or infected by the antigen, which is truly foreign.

Question 29

Releast of a sequestered antigen

Answer 29

Note that in the special case of sequestered antigens, the antigen cannot get out into the general system, and therefore is not normally immunogenic, but if an immune response does get initiated, then the response can usually get into the place where the antigen was sequestered. Ex) Mumbs and boys testis

Question 30

epitope spreading

Answer 30

With sequestered antigen… Early in the disease antibodies are made to just one or two epitopes of some “self” protein. With time, more epitopes, and more proteins are involved.

Question 31

Failure or regulatory mechanisms

Answer 31

proper balance between Th1, Th17, Tfh, Th2, and Treg activity assures that immune responses are appropriate. Does this balance get perturbed in some way, so that some responses are exaggerated, and eventually self/non-self discrimination breaks down? This is an area of intense speculation lately.

Question 32

Diagnosis

Answer 32

In general the hallmark test is ►immunofluorescence. You can do a direct test, looking for antibody in the patient’s tissues, if you happen to have a sample of the patient’s tissues. OR if you only have the patient’s serum, you can look for antibody in it by an indirect immunofluorescence test, using normal human tissue (LOOK THIS UP)

Question 33

Graves Disease

Answer 33

Thyroid stimulating hormone usually releases and then there is a negative feedback loop to regulate it. Now in graves TSH receptor is bound by antibody and tricks it into thinking it is TSH and then stimulated the cell and then pours of T3, T4 and these go up to the parathyroid and there is not feedback loop to stop it. Have to immunosuppress your patient, BUT NOT A GOOD TREATMENT DO. SO take out THYROID.