Autoimmunity

Question 1

describe the adaptive immune response

Answer 1

The adaptive immune response or adaptive immunity is the response of antigen specific lymphocytes to antigen, including the development of immunological memory. Adaptive immune responses are generated by clonal selection of lymphocytes. Adaptive immune responses are distinct from innate and nonadaptive phases of immunity, which are not mediated by clonal selection of antigen-specific lymphocytes. Adaptive immune responses are also known as acquired immune responses.

Question 2

what are the 2 compnents of the adaptive immune response?

Answer 2

cell mediated

humoral immunity

Question 3

main responders of the innate immune system

Answer 3

NK

complement

Question 4

main cells in cell mediated response

Answer 4

T cells

Question 5

main cells in humoral response

Answer 5

b cells

Question 6

describe the innate immune system

Answer 6

The innate immunity acts as an initial response to microbes, and is found in a variety of vertebrates, insects and even plants. It initiates the process of tissue repair in damaged cells and stimulates the ADAPTIVE immune response. An infected cell by a pathogen secretes Type 1 Interferons (IFNα/β) that directly interfere with viral replication. They also down regulate MHC1 markers on cell surfaces making them seem less “self”. This in turn alerts circulating natural killer cells that secrete Type II Interferon (IFNγ) and granules containing perforin and apoptosis inducing enzymes. This lyses and kills the cell before the virus has time to replicate further. IFNγ then activates Sentinel cells

Question 7

what are sentinel cells?

Answer 7

cells in the body’s first line of defence which embed themselves in tissues

Question 8

give examples of sentinel cells

Answer 8

kupffer cells 
langerhans cells (skin/mucosa)
alveolar macrophages 
microglia
dendritic cells
mass cells and specialised T cells
macrophages

Question 9

activation of sentinel cells

Answer 9

IFN-g

PAMP

Question 10

what do activated sentinel cells cause

Answer 10

inflammation
complement cascade
increase temperature

Question 11

where are complement protiens produced?

Answer 11

liver

Question 12

describe the actions of cytotoxic T cells

Answer 12

The actions of cytotoxic T cells are the most direct. These recognize any of the body’s cells that are infected with viruses, which replicate inside cells, using the biosynthetic machinery of the cell itself. The replicating virus eventually kills the cell, releasing new virus particles. Antigens derived from the replicating virus are, however, displayed on the surface of infected cells, where they are recognised by cytotoxic T cells. These cells can then control the infection by killing the infected cell before viral replication is complete. Cytotoxic T cells typically express the molecule CD8 on their cell surfaces.

Question 13

actions of non cytotixic t cells

Answer 13

Other T lymphocytes that activate the cells they recognize are marked by the expression of the cell-surface molecule CD4 instead of CD8. Such T cells are often generically called helper T, or TH cells, but this is a term that we will use for a specific subset of CD4 T cells. CD4 T lymphocytes can be divided into two subsets, which carry out different functions in defending the body, in particular from bacterial infections. The first subset of CD4 T lymphocytes is important in the control of intracellular bacterial infections. Some bacteria grow only in the intracellular membrane-bounded vesicles of macrophages; important examples are Mycobacterium tuberculosis and M. leprae, the pathogens that cause tuberculosis and leprosy. Bacteria phagocytosed by macrophages are usually destroyed in the lysosomes, which contain a variety of enzymes and antimicrobial substances. Intracellular bacteria survive because the vesicles they occupy do not fuse with the lysosomes. These infections can be controlled by a subset of CD4 T cells, known as a TH1 cells, which activate macrophages, inducing the fusion of their lysosomes with the vesicles containing the bacteria and at the same time stimulating other antibacterial mechanisms of the phagocyte (Fig. 1.26). TH1 cells also release cytokines and chemokines that attract macrophages to the site of infection.

Question 14

what effect does antigen presentation have on T cells?

Answer 14

stimulates them to become either cytotoxic CD8 cells or helper CD4 cells

Question 15

where are central memory cells found?

Answer 15

lymph nodes

Question 16

what are effector memory cells?

Answer 16

Lack LN homing receptors (L-selectin)

Express CD45RA, marker found on Native T cells

Question 17

what are tissue memory cells?

Answer 17

Occupy tissues to protect against pathogens

Question 18

describe central memory t cells

Answer 18

Central memory T cells (TCM cells)= express CD45RO, C-C chemokine receptor type 7(CCR7), and L-selectin (CD62L). Central memory T cells also have intermediate to high expression of CD44. This memory subpopulation is commonly found in the lymph nodes and in the peripheral circulation. (Note- CD44 expression is usually used to distinguish murine naive from memory T cells).

Question 19

describe effector memory T cells

Answer 19

Effector memory T cells (TEM cells and TEMRA cells)= express CD45RO but lack expression of CCR7 and L-selectin. They also have intermediate to high expression of CD44. These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues. TEMRA stands for terminally differentiated effector memory cells re-expressing CD45RA, which is a marker usually found on naive T cells.

Question 20

describe tissue resident memory t cells

Answer 20

Tissue resident memory T cells (TRM)= occupy tissues (skin, lung, gastrointestinal tract, etc..) without recirculating. One cell surface marker that has been associated with TRM is the integrin αeβ7. These cells are thought to play a major role in protective immunity against pathogens

Question 21

what conditions are tissue resident T cells dysfunctional?

Answer 21

psoriasis
RA
IBD

Question 22

define tolerance in regards to immunology

Answer 22

a state of unresponsiveness of the immune system to self

Question 23

describe the mechanism of central tolerance in regards to immunology

Answer 23

Tolerance sensitive stage of maturation CD4+ and CD8+ thymocytes
Enhanced by IL-10 and TGF-Ɓ
Inhibited by Leuktriene, IFN-Ɓ and TNF-Ɓ
Central tolerance is the main way the immune system learns to discriminate self from
non-self.
The deletion threshold is much more stringent for T cells than for B cells since T cells
alone can cause direct tissue damage. Furthermore, it is more advantageous for the
organism to let its B cells recognize a wider variety of antigen so it can produce
antibodies against a greater diversity of pathogens. Since the B cells can only be fully
activated after confirmation by more self-restricted T cells that recognise the same
antigen, autoreactivity is held in check

Question 24

where does central tolerance take place? in regards to immunology

Answer 24

thymus

Question 25

what controls peripheral tolerance? in regards to immunology

Answer 25

inhibition of expression of the immune response | Treg cells = Th17

Question 26

describe the mechanism of peripheral tolerance in regards to immunology

Answer 26

Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.) Clonal deletion (apoptotic cell death); clonal anergy (functional inactivation without cell death); clonal ignorance (failure to recognize or recognition of antigens without costimulation); suppression of lymphocyte activation and effector functions by regulatory lymphocytes Treg cells are not the only cells that mediate peripheral tolerance. Other regulatory immune cells include T cell subsets similar to but phenotypically distinct from Treg cells Oral tolerance is antigen-induced specific suppression of humoral and cell-mediated immunity to an antigen following oral administration of that antigen as a consequence of anergy of antigen-specific T cells or the formation of immunosuppressive cytokines such as transforming growth factor-β. Oral tolerance may inhibit immune responses against food antigens and bacteria in the intestine. Based on the quantity of antigen fed, orally administered antigen may induce regulatory cells that suppress the antigen-specific response (low doses) or inhibit antigen-specific T cells by induction of clonal anergy (high doses)

Question 27

name the "professional" APCs

Answer 27

DCs macrophages B cells

Question 28

name the atypical APCs

Answer 28

mast cells basophils eosinophils ILC3s

Question 29

name the key features of dendritic cells and macrophages in regards to APC

Answer 29

phagocytoic express receptors for apoptotic cells, DAMPs and PAMPs localise to tissues localise to t cell zone of lymph nodes following activation (DCs) constitutively express high levels of MHC class II and antigen processing machinery express co-stimulatory molecules following activation

Question 30

name the key features of b cells in regards to APC

Answer 30

``` internalise antigencs via BCRs constitutievely express MHC class II and antigen processing machinery express co stimulatory molecules following activation ```

Question 31

name the key features of the atypical APCs

Answer 31

``` inducible expression of MHC class 2 antigen presenting functions limited to specific immune environments (especially type 2 immune settins) lack of complelling evidence that they can activate naive CD4 T cells in an antigen specific manner ```

Question 32

define autoimmunity

Answer 32

physiological autorecognition with secondary epiphenomena

Question 33

define autoimmune disease

Answer 33

immune response contributing to tissue/organ damage often exist as a mix of differnet autoimmune reactions environment and genetics play a key role

Question 34

factors causing autoimmunity: genetic

Answer 34

Human Leukocyte Antigen can correlate with certain diseases Very seldom is there an individual, pin-pointable gene Though in some instances the presence of single gene defects such as FAS/FasL, AIRE, FOXP3, Complement Genes (Lupus) can cause autoimmune disease

Question 35

factors causing autoimmunity: hormonal

Answer 35

Women more likely to be affected than men (as high as 10/1) | SLE 10x more common in women than men in reproductive years, but only 2x more common in early/later life

Question 36

factors causing autoimmunity: enviroment

Answer 36

UV Sun exposure can incite apoptosis in SLE, exposing T-cells to anti-nuclear antibodies (therein seen as foreign) For example, Klebsiella pneumoniae and coxsackievirus B have been strongly correlated with ankylosing spondylitis and diabetes mellitus type 1, respectively. This has been explained by the tendency of the infecting organism to produce super-antigens that are capable of polyclonal activation of B-lymphocytes, and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below). Infections break down the tolerance Its postulated that infections can actually LOWER your risk of autoimmune disease, seen often in areas of high endemic infection rates. Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions that simulate autoimmune diseases. The most striking of these is the drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the symptoms in a patient.

Question 37

function of t cells

Answer 37

T cells destroy intracellular pathogens by killing infected cells and by activating macrophages but they also have a central role in the destruction of extracellular pathogens by activating B cells.

Question 38

in regards to cell mediated autoimmunity what is T cells bypass

Answer 38

Normally, B-cells are activated and diffentiation initiated by alerted Tcells Rarely, this is bypassed (i.e. Infections) producing Superantigens These initiate polyclonal activation of B-cells, or even of T-cells, by directly binding to the β-subunit of T-cell receptors in a non-specific fashion

Question 39

in regards to cell mediated autoimmunity what is T/B cell discordance

Answer 39

T Cells and B-cells are assumed to respond to the same antigen When they don’t B-cells can use any T-cell to do their dirty work In coeliac disease B cells for transglutamine are helped by T cells recognising gliadin.

Question 40

what may cause t cell bypass and T/B cell discordance

Answer 40

The basis for these clinical complications is unclear, but are thought to be caused by a breakdown in immune tolerance in which a lack of T regulatory cells or the participation of Th17 cells plays a critical role in the pathogenesis of these disorders

Question 41

cell mediated autoimmunity: type 1 diabetes

Answer 41

autoreactive t cells against pancreatic islet cell antigens, leading to destruciton and non-production of insulin

Question 42

cell mediated autoimmunity: crohn's disease

Answer 42

triggered by foreign pathogens leading to APC presentation autoreactive T cells against intestinal flora antigens leading to lymphocyte infiltration of exocrine glands For reasons not clearly understood, pathogens make it past the mucosa in the gut, and are engulfed by APCs. The cytokine reaction from T-Helper cells is dysfunctional and exaggerated, leading to lots of Macrophages creating proteases and platelet activating factors, which causes inflammation

Question 43

gene involved in inherited crohn's

Answer 43

NOD2

Question 44

cell mediated autoimmunity: psoriasis

Answer 44

autoreactive t cells against skin associated antigens | constant turn over of skin and inflammation without infection

Question 45

describe mechanisms involved in coeliac disease

Answer 45

In coeliac disease B cells for transglutamine are helped by T cells recognising gliadin (an amino acid sequence in Gluten). Secretory IgA in mucosal membrane (normally a marker of immune cell destruction, crosses to lamina proprieta. Macrophages uptake these TTG antibodies, express MHCII antibodies (HLA-DQ2) CD4+ TH Cells release IFNγ and TNF – destroying villi, CD8+ TC destroy damaged endomysial cells The basis for these clinical complications is unclear, but are thought to be caused by a breakdown in immune tolerance in which a lack of T regulatory cells or the participation of Th17 cells plays a critical role in the pathogenesis of these disorders

Question 46

describe antibody mediated autoimmunity

Answer 46

antibody binds to targets leading to damage by Fc receptor macrophage with or without complement lysis type 2 hypersensitivity reaction Antibody binds to targets leading to damage by FC receptor macrophage and or complement lysis Can also lead to immune complex formation and deposition, activating phagocytes and causing damage (SLE) You can also have a direct effect of the autoantibodies on the autoantigen affecting its function (Pemphigis, Myaesthenia)

Question 47

describe goodpasture syndrome

Answer 47

Collagen, the most abundant protein in the human body, is one of 6 types – alpha 1- 6. Type 4 collegen comes in 3 forms (which you don’t need ot commit to memory. Alpha 3/4/5 found in lungs and kidneys, and IgG antibodies react to the alpha 3 (after some damage some event) C1 attaches to collagen and activates/cleaves other elements. This attracts other cells (inc Neutrophils) that cause ezyme release and damage. Genetic risk - HLA-DR15 Environmental risk – Infection/Smoking/Solvents (dry cleaning). Places likely to be damaged are lung and kidneys type 4 collagen (kidney, lungs, skin) gets attached to by antibody, complement activation, immune response with NK cells, white cells come along degranulate and kill the BM in each of the tissues. causing pulmonary haemorrhage renal damage - total effacement and sclerosis of glomerulus need aggressive immunotherapy anti GBM antibody

Question 48

describe immune complex autoimmunity

Answer 48

antigen antibody/immune complex formation and deposition, activating phagocytes and causing damage type 3 hypersensitivity rreaction A fully differentiated B cell called a plasma cell secretes antibodies into serum, and has antibodies bound to it’s cell surface to act as receptors When an antigen cross links 2 surface antibodies on the plasma cell, it absorbs it, and offers a piece of it to T Helper cells. They join via stimulatory CD4 and CD40 Ligands and the B-cell releases cytokine which switch it’s Immunoglobulin class This solusblr Antibody binds to targets leading to damage by FC receptor macrophage and or complement lysis (AIHA, ITP, Anti-GBM

Question 49

what type of hypersensitivity is immune complex autoimmunity?

Answer 49

3

Question 50

what type of hypersensitivity is antibody mediated autoimmunity

Answer 50

2

Question 51

describe the mechanisms involved in SLE

Answer 51

failure of tolerance allowing self reactive B/T cells to circulate leaked autoantigen is presented to B cell, passed to T helper cells and antibodies to DNA made A failure of self-tolerance allows a B-cell to react to leaked DNA auto-antigen from a damaged cell If a T-cell that is also specific to this, it begins to secrete anti-dsDNA antibodies to be produced

Question 52

describe immune complex autoimmunity

Answer 52

Small antigen-antibody complexes aren’t big enough to be picked up by the macrophages, and as such they ionically deposit in basement membrances. This then activates Complement, which recruits Neutrophils via chemochines, who de-granulate and cause tissue inflammation and necrosis. This releases more DNA, and makes matters worse. As blood if filtered in kidneys, and the synovium to create synovial fluid, the damage happens there.

Question 53

describe innate recruitment

Answer 53

Antibody binds to targets leading to damage by FC receptor macrophage and or complement lysis (AIHA, ITP, Anti-GBM) Can also lead to immune complex formation and deposition, activating phagocytes and causing damage (SLE) You can also have a direct effect of the autoantibodies on the autoantigen affecting its function (Pemphigis, Myaesthenia)

Question 54

describe myasthenia Gravis

Answer 54

disease against NMJ autoreactive t cells and b cell ACH receptor antibodies weakness and fatiguability Myasthenia gravis is an autoimmune disease which results from antibodiesthat block or destroy nicotinic acetylcholine receptors at the junction between the nerve and muscle.[1] This prevents nerve impulses from triggering muscle contractions. Complement activation also causes local inflammation ACH Receptor antibodies in 85%. Thymomas are cancers of the Thymus, and can cause autoantibody release

Question 55

what is myasthenia gravis associated with?

Answer 55

thymoma

Question 56

treatment of myasthenia gravis

Answer 56

cholinesterase inhibitors immunosupression thymoma

Question 57

describe graves disease

Answer 57

Autoantibodies against the Thyroid stimulating hormone receptor. Activates the TSH and over-produces Thyroid hormones overrides negative feedback

Question 58

describe the concept of molecular mimicry

Answer 58

The concept of molecular mimicry describes a situation in which a foreign antigen can initiate an immune response in which a T or B cell component cross-recognizes self. The cross reactive immune response is responsible for the autoimmune disease state.[14] Cross-reactive immune responses to self were first described for antibodies.

Question 59

describe molecular mimicry in rheumatic fever

Answer 59

An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens, and amplify the immune response. The idea of molecular mimicry arose in the context of Rheumatic Fever, which follows infection with Group A beta-haemolytic streptococci. Although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). Moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. It remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium

Question 60

describe MS in regards to immunology

Answer 60

t cells specific to myelin cross the BBB and release cytokines BBB damage, macrophage and Tc cell migration attacks oligodendrocyte despite Treg cells allowing healing, eventually damage becomes worse associated to HLA-DR2 and vit D deficiency

Question 61

treatment of autoimmune disease

Answer 61

``` immunosuppressive therapy anti-inflmmatory therapy plasmapheresis stem cell/bone marrow transplant? replacement of lost physiological factor organ/tissue/mechanical graft ```