Immunology 2015 review new by Medicos 143

FINAL REVIEW QUESTIONS 2015

BHAGATH M S

RAJEEV BISWAS

1. GALT (Gut-associated lymphoid tissue) The digestive tract's immune system is often referred to as gut-associated lymphoid tissue (GALT) and works to protect the body from invasion. The GALT is made up of several types of lymphoid tissue that store immune cells, such as T and B lymphocytes, that carry out attacks and defend against pathogens.

2. Peyer’s Patches  The uncapsulated lymphoid nodules  Present in ideal sub-mucosa of the small bowel  They serve to detect that diffuse across the intestinal epithelium

3. MIS (Mucosal lymphoid system) All the organized and diffused lymphoid tissues found in sub-mucosal region of the body can be reviewed as single functional unit called Mucosal lymphoid System.

Generating sIgA

4. APCs Cells that constitutively express class II MHC molecules and present Ag to helper T cells. That is a “professional”APC. o Dendritic cells( DC), Macrophages (M), B cells o Each has unique properties that make it important for particular aspects of the immune response.

5. Immunological Tolerance • •

When specific lymphocytes encounter antigens, the lymphocytes may be activated, leading to immune response, or the cells may be inactivated or eliminated, leading to tolerance. Tolerance is immunologically specific and results from the recognition of Ag by specific lymphocytes.

6. Programmed cell death (apoptosis) Under some circumstances, cells respond to environment or internal signals by committing suicide ---a phenomenon known as PROGRAMMED CELL DEATH, or APOPTOSIS

7. Systemic lupus erythematosus (SLE)  SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) is a chronic autoimmune connective tissue disease that can affect any part of the body.  As occurs in other autoimmune diseases, the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage.  SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system.

8. Epitopes or antigenic determinants  An EPITOPE is the specific site to which a particular Ig or TCR binds. It follows that every immunogen must contain one or more epitopes that enable it to serve as an Ag.  Epitope = Antigenic Determinant = The part of an antigen molecule that interacts with the lymphocyte’s receptor for antigen (B cells / antibody; T cells / TCR)

9. B and T Cells Epitopes  T CELL EPITOPES: o The region that are recognized by TCRs are called T cell epitopes. o T cells only recognize their epitopes in association with MHC molecules on cell surfaces.  B CELL EPITOPES: o The regions that are recognized by immunoglobulins are called B cell epitopes. o Immunoglubulins recognize the epitopes individually unlike the T cells.

10. Common Ag and Cross Reaction o Some Ag can not only react with Ab or activate lymphocytes by themselves to induce an immune response, but also can react with Ab or activate lymphocytes by other inducing, there Ag frequent strip multi-Ag epitope. o These different Ag contain sameness or similitude Ag epitope is COMMON Ag. o Antigen or activate Lymphocyte react with sameness or similitude Ag Epitope in different Ag is CROSS REACTION.

11. Heterophilic Ag and Autoantigen  Heterophilic Ag  It is a kind common Ag, exists in human, animals and microorganism, as well as Forssman Ag.  For example, there are common Ag in a strain hemolytic streptococcus surface component and cardiac muscle self-tissue, therefore, hemolytic streptococcus-induce Ab may crossly react with heart, kidney tissue, and results in nephritis and cardiac muscle inflammation.  Autoantigen.  In common, immunity system does not response against self-tissues or cells, in other words, it gets tolerance to its own body.  In some pathology (such as enshrouded or isolated Ag; self-Ag occur change or decorated) , oneself component can induce body to self immune response.

12. Central T Cell Tolerance Self tolerance induced in generation lymphoid organs as a consequence of immune self-reactive lymphocytes recognizing self-antigen is called CENTRAL TOLERANCE.

13. Peripheral tolerance Self tolerance induced in the peripheral sites as result of mature self reactive lymphocytes encountering self antigen under a particular condition, is called PERIPHERAL TOLERANCE

14. Positive selection Phenomenon which permits or ensures the survival of those T-cells that recognize the self-MHC molecules, thus it is responsible for creation of self-MHC restrictive receptors of T-Cells.

15. Negative-selection of thymocytes Phenomenon that eliminates T-cells that react strongly or show high affinity with the self-MHC molecules.

16. Immune complex disease (ICD)  Immune complex disease local or systemic disease caused by the formation of circulating immune complexes and their deposition in tissue, due to activation of complement and to recruitment and activation of leukocytes in type III hypersensitivity reactions. OR  Immune complexes that cause disease may be composed of either seif antigens or foreign antigen with bound antibodies.  Pathologic features of disease caused by immune complexes refects the site of immune complexes deposition and are not determined by cellular source of antigen  Immune complex mediated disease tend to be systemic with little or no specificity for a particular tissue or organ.  Example :: Serum sickness, Auto immune reaction [eg:: arthiritis], SLE

17. TD-Ag Generally, Ag contact alone is insufficient to activate B cells because most protein Ag depends on Both T cells and B cells recognizing the Ag in a linked fashion. This type of Ag is called T-dependent Ag (TD-Ag). o By manipulating the cell populations in these experiments, it was shown that Th cells are responsible for recognizing the carrier, whereas the B cells recognize hapten (incomplete Ag ). o The secondary responses to TD-Ag is far stronger and has a large IgG component.

18. Localized Anaphylaxis  Localized anaphylaxis is a hypersensitivity reaction which is limited to a specific target tissue or organ.  The tendency to manifest localized anaphylactic reacrtions is inherited & is called atropy. Atopic allergies include a wide variety of IgE mediated disorders, including asthma, hay fever, atopic dermatitis and food allergies

19. Graves disease  A type II hypersensitivity reaction involving receptor Binding.  Antibodies to Thyroid Stimulating Hormone (TSH)- Receptor, stimulate thyroid hormone production, block of TSH feedback inhibition.  Result is excessive thyroid hormone production.  Binding this auto-antibodies to receptors mimics the normal action of TSH, activating adenylate cycclase, resulting in production of thyroid hormone.

20. Goodpasture’s syndrome Goodpasture syndrome is an autoimmune disorder of unknown cause that is characterized by the presence of circulating antibodies in the blood which attack the basement membrane of the kidney's glomeruli and the lung's alveoli and that is marked initially by coughing, fatigue, difficulty in breathing, and hemoptysis progressing to glomerulonephritis and pulmonary hemorrhages.

21. Asthma  Common manifestation of Localized anaphylaxis is ASTHMA  Air-borne or Blood-borne allergens such as pollens, dust fumes, insect products or viral antigens triggers an asthmatic attack.  Asthma is triggered by degranulation of mast-cell with release of mediators, resulting contraction of bronchial smooth muscle leads to broncho-constriction.  Airway edema, mucus secretion and inflammation contribute bronchial constriction and airway obstruction. OR  Asthma, A chronic lung disorder that is marked by recurring episodes of airway obstruction (as from bronchospasm) manifested by labored breathing accompanied especially by wheezing and coughing and by a sense of constriction in the chest, and that is triggered by hyperactivity to various stimuli (as allergens or rapid change in air temperature).

22. Serum Sickness Serum sickness is an allergic reaction to the injection of foreign serum manifested by hives, swelling, eruption, arthritis, and fever called also SERUM DISEASE.

23. Contact Dermatitis  CONTACT DERMATITIS is the name for any skin inflammation that occurs when the skin's surface comes in contact with a substance originating outside the body.  There are two kinds of contact dermatitis o Irritant o Allergic.

24. NK cells     

Are large granular lymphocytes, They do not require thymus for their development. They kill using PERFORIN. They rapidly produce cytokines upon ligand recognition. They are important in resistance against pathogens.

 They show CD8 markers.

25. γδT cells  Their discovery was accidental and function remains unclear  The function of :T cells is relatively unknown, one of there striking feature is lack of diversity in their receptors esp. in the cells.  Found in surface epithelia(receptors are homogenous in one epithelium).

26. TI-Ag  Some Ag do not require the presence of helper T cells, however, and are called T-independent Ag( TI-Ag).  These Ag typically fall into either of two categories, with different mechanistic properties. TI-Ag and TI-2Ag

27. DC  Dentritic Cells, DC arise from either myeloid or lymphoid lineages of the bone marrow.  They are responsible for launching most adaptive immune responses and for primary responses.  The also act as antigen presenting cells.

28. TCR- CD3 complex  T lymphocytes do not see soluble antigens but rather recognize antigens bound to specialized molecules on surface of other cells.  The α-β TCR dimmer recognize peptides bound to MHC molecules .  The α-β dimmer is associated with a complex of proteins designated CD3.  The CD3 chains are not polymorphic they are involved in signal transduction and thus allow TCR to convert the recognition of antigen MHC into intracellular signals for activation.

29. Mature B cells  Mature B cells are found in peripheral lymphoid organs they are characterized by expression of IgD & IgM.  In addition to IgM, the earliest mature cells in the Bone marrow expresses Low levels of IgD  These cells are exported from the Bone marrow to peripheral Lymphoid organs, where the expression of membrane IgD increases.

30. Recombination signal sequence (RSS) Sequencing upstream and downstream of U, D and J elements revealed conserved sequences of 7, 23, 9 and 7, 12 and 9 nucleotides.

31. Pattern-recognition receptors (PRRs)  PRR: pattern recognition receptor  some receptor existed on surfaces of innate immune cells and serum, which can recognize and bind common molecular structures of pathogenic microorganisms or apoptotic cells of host.

32. MHC restriction MHC restriction of T cell: Any individual’s T cells respond to a specific MHC allele expressed by that individual, that is to “self” MHC.

o CD8+ T cells, class I restricted o CD4+ T cells, class II restricted

33. PAMPs  PAMP: pathogen associated molecular pattern  ligands of PRR, mainly refers to highly conserved common molecular structures existed on surfaces of some pathogenic microorganisms.

34. GM-CSF o GM-CSF: granulocyte-monocyte colony-stimulating factor o Cytokines that support the production of particular mature blood cell types from pluripotent stem cells or committed progenitors in the bone marrow.

35. Affinity maturation  Affinity maturation is the observation that antibodies produced later in an immune response tends to have higher affinity for target antigen than those produce earlier.  Especially antibody produced in secondary response has higher affinity than primary response.  Cell selection process is throught to account for this phenomenon.  CD4 expression indirectly leads to Ag affinity maturation.

36. ITAM  Immunoreceptor Tyrosine-based Activation Motif  Is a conserved sequence composed of two copies of sequence tyrosine X-X leucine.  Found in cytoplasmic tails of various membrane protein in immune receptor that are involved in signal transduction.  Activating receptors : initiating transduction of active signals

37. ITIM  Immunoreceptor Tyrosine-based Inhibitory Motif  Is a conserved sequence of six amino acids (iso-leucine-X-tryosine-X-Xleucine)  Is found in the cytoplasmic tails of many inhibitory receptors of the immune system countering the action of ITAM.  Suppressing receptors: inhibiting transduction of Active signals

38. BCR  Surface markers of B cells which can recognize the antigen peptides are called BCR.  BCR can recognizing the antigen without the association of MHC  BCR recognizes and finds antigen epitope on the surface of antigen but cannot itself generate a signal.  The signaling function of CD3 is carried out by disulphide- bonded heterodimers of Igα and Igβ.

39. Opsonization  This process involves the coating of foreign particle with specific complement proteins fragments that can be recognized by the receptors for the fragments on phagocytic cells.  IgG is an opsonizing antibody. It reacts with epitpoes on microorganisms via its Fab regions but it is the Fc region of IgG has binds to macrophages phagocytes.

40. CDRs, complementary-determining regions  Shorter regions of extreme variability each containing 9-12 amino acids are called hyper variable regions.  VH and VL regions each contain 3 hyper variable regions. Hyper variable regions are also called CDRS (complementary-determining regions).

41. Monoclonal antibody , mAb  Antibody producing clone of hybrids is called hybridoma and the antibodies produced by hybridoma are called monoclonal antibody.  Monoclonal antibodies that are radioactively labeled that recognize the tumor surface antigens.

42. Membrane attacking complex, MAC The terminal sequence of the compliment activation involves C5b, C6, C7, C8 and C9 this component interacts to form a structure termed as MAC 1. C6 binding to C5b on a cell surface. 2. C7 then binds to C5b and C6 and undergoes a hydrophobic structural transition. 3. C8 binding to C5bC6C7 creating a small pore. 4. 10-16 C9s can be polymerized by a single C5bC6C7C8 complex, forming C5678(9)n, termed MAC

43. HLA  Human Leukocyte Antigen (HLA)  Human MHC was first studied using Antibody reaction with WBC called HLA

44. Cluster of differentiation, CD o Cell surface molecules can be recognized by particular monoclonal antibodies. o All of the monoclonal antibodies that react with a particular membrane molecule are grouped together as a cluster of differentiation (CD)

45. Anchor residues Some amino acid residues of peptides anchor the peptide into the pockets within the groove of the MHC molecule.

46. ADCC • • • •

Antibody-Dependent Cell-Mediated Cytotoxicity is a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies. It is one of the mechanisms through which NK cells recognize their targets. In this case the cells are activated by a low affinity Fc receptor that recognizes clustered antibody decorating a cell surface OR

Antibody binds antigens on the surface of target cells

Fc receptors on NK cells recognize bound antibody

Crosslinking of Fc receptors signals the NK cell to kill the target cell

Target cell dies by apoptosis and/or membrane damage

o NK cells kill rapidly when they detect targets, for example, antibody coated cells. o In this case the cells are activated by a low affinity Fc receptor that recognizes clustered antibody decorating a cell surface.

47. TNF  Tumor Necrosis Factor, refers to a group of cytokine family  They are classified into TNFα and TNFβ  They can induce hemorrhagic necrosis of certain tumors

48. IFN IFN (INTERFERON) is large family of secretory proteins.  They can interfere with viral replication  The major function are:: o Anti virus o Modulate immune response

49. CSF  COLONY STIMULATING FACTOR  Cytokines that support the production of particular mature blood cell types from pluripotent stem cells or committed progenitors in the bone marrow.  Are classified as :: o GM-CSF: granulocyte-monocyte colony-stimulating factor o M-CSF: monocyte colony-stimulating factor o G-CSF: granulocyte colony-stimulating factor o EPO (erythropoietin) o SCF (stem cell factor)

50. IL-2 o o o o

INTERLEUKIN-2 Cytokine secreted by TH1 cells. It targets antigen prime TH and Tc cells Major functions are::  Induces proliferation  Supports long term growth

51. Immunologic Synapse  Is the interface between an antigen-presenting Cell(APC) and a T lymphocyte. It Concentrates TcR at the center of the interaction and stabilizes the contact.  There are 2 zones: o Central-supramolecular activation complex (c-SMAC) o Peripheral zone (p-SMAC)

52. AICD  Activation-induced cell death (AICD) in T lymphocytes, in which activation through the T-cell receptor results in apoptosis.  AICD can occur in a cell-autonomous manner and is influenced by the nature of the initial T-cell activation events.  It plays essential roles in both central and peripheral deletion events involved in tolerance and homeostasis.

53. FasL  Apoptosis can be induced by various signals inside and outside the cell.  Important recetor for death signals is a surface protein cell FasL (or CD95L).  Many cell exress Fas when they are suicide prone because it allows them to be killed by other cells expressing a surface protein called FasLigand (FasL) OR  Fas ligand (FasL or CD95L) is a type-II transmembrane protein on the surface of cytotoxic T cells that binds to its receptor, Fas, on the surface of other cells, initiating apoptosis in the target cell.

54. TCR  TCR is found on the surface of T Lymphocytes [membrane bound]  TCR is specific not for antigen alone but for antigen combined with a molecule encoded by MHC OR  The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is, in general, responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules.

55. ELISA  ELISA is Enzyme Linked Immuno Sorbent Assay  It is a technique used in Immunology to detect the presence of an antibody or antigen in a sample.  It is the main tool for diagnosis of AIDS, HBV etc OR  The T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is, in general, responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules.

56. Insulin Dependent Diabetes Mellitus (IDDM) Is also called type 1 diabetes mellitus, it is an organ-specific autoimmune disorder which affects the pancreatic islets.in IDDM there is T-cell mediated destruction of insulin producing β cells of islets of Langerhans this leads to the deficiency of insulin.

57. Systemic lupus erythematosus (SLE)  Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disease that can affect any part of the body.  As occurs in other autoimmune diseases, the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage.  SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system.

1. What is the role of the immune system?  Eliminate foreign (dangerous) substance ( tissue, cell or molecule)  Accept or tolerate self (useful) substance.  Main functions are::    

To provide defense against the foreign substance. To kill the foreign substances by inducing immune response. Accept or Tolerate Self (useful) substance. Protection from certain disease, particularly infectious disease.

2. What happens when the immune system doesn’t work properly? > Infectious disease > cancer > autoimmunity > hypersensitivity etc.

3. What is the immune system discrimination ? Immune system has ability to distinguish between self & non-self it is called as immune system discrimination.  Infectious(dangerous)non-self(microbial pathogens)  Non-Infectious non-self (different kinds of foods etc)  Infectious self(latent virus)  Non-infectious self (normal tissues)

4. What is the Clonal Selection? According to the theory 1. individual lymphocyte expresses membrane receptors that are specific for a distinct Ag. This unique receptor specificity is determined before the lymphocyte is exposed to the Ag. 2. Binding of Ag to its specific receptor activates the cell, causing it to proliferate into a clone of cells that have the same immunologic specificity as that of the parent cells. 3. Lymphocytes with receptors against self are deleted from an early stage or became forbid clone and are absent from the repertoire of mature lymphocytes.

During development progenitor cells give rise to large numbers of lymphocytes, each with a different specificity

Pool of circulating small lymphocytes

Proliferation & differentiation of pathogen- activated lymphocytes to form a clone of effector cells

Effector cells eliminate pathogen

Clonal selection of Lymphocyte 1. A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce

2. immature lymphocytes with many different antigen receptors. Those that bind to

3. antigens from the body's own tissues are destroyed, while the rest mature into

4. inactive lymphocytes. Most of these will never encounter a matching

5. foreign antigen, but those that do are activated and produce 6. many clones of themselves

5. What is the innate immunity? Innate > Possessed at birth; inborn. > Possessed as an essential characteristic; inherent. > Of or produced by the mind or body or genes rather than learned through experience. Immunity Inherited, acquired, or induced resistance to infection by a specific pathogen.

6. What is the adaptive immunity? Immunity that is no inborn, but develops after the antigen exposure. Characteristics:1. Survivors of infection donâ&#x20AC;&#x2122;t get infected again.

2. 3. 4. 5. 6. 7. 8.

Childhood mortality from infections Communications b/w lymphoid and myeloid cells. Memory & specificity Receptors for antigen on lymphocytes Clonal selection Slow response (days to week) Can be further distinguished as Cellular & Humoral

7. Comparison of Innate Versus Adaptive Immunity Recognition mechanisms of INNATE immunity Rapid response (hours) Invariant Non-specific (Limited number of specificities) Constant during response

Recognition mechanisms of ADAPTIVE immunity Slow response (days to weeks) Variable Specific (Numerous highly selective specificities) Improve during response

Common effector mechanisms for the destruction of pathogens

8.Humoral Immunity and Cellular Immunity Humoral Cell line Product Protection against

Cellular

B cells, Plasma Cells Antibody Bacteria viruses

T cells Sensitized Cells Viruses, mycobacteria, fungi OR

4. HUMORAL IMMUNITY a. Secreted products of B lymphocytes b. Antibodies or Immunoglobulins (Ig) c. Some soluble macromolecules (proteins) that circulate in blood and ECF, making these fluids inhospitable to foreign invaders when all cells have been removed; cell-free defense of this type are Humoral Immunity d. The cells responsible for antibody production are B-Lymphocytes. e. This type of immunity protects well against Bacteria virus, & other invades and toxins. 5. CELLULAR IMMUNITY a. T lymphocytes. T cell receptor b. Cytokines and cell-cell contact c. Some specialized cells that have the ability to recognize, sequester and eliminate various types of organisms or harmful substances; defenses provided by such cells are collectively known as cellular immunity. d. Cell responsible for the cellular immunity are T-Lymphocytes especially with antigens or infecting organism through specialized receptors. e. This type of immunity protects well against Virus, Fungi etc.

9.What is the primary lympoid organs ?and concise answer their major function please.  BONE MARROW & THYMUS are considered as the primary Immune organs and there function is usually the PRODUCTION OF T & B LYMOHOCYTES.  Main function is the denovo production of short-lived, quiescent native lymphocytes that are then released into the periphery. BONE MARROW:: T & B lineage cells both arise from a subset of hematopoietic stem cells(HSC) in the bone marrow.  Human B lymphocytes development takes place entirely within the bone marrow. THYMUS: Thymus consists of thymic stromal cells(TSC) and thymocytes .  T cells develop from immature precursors that leave marrow travel through the blood stream to the Thymus.

B-CELL

T-CELL

10.What is the peripheral lympoid organs ?and concise answer their major function please. Lymph nodes & spleen are peripheral or secondary lymphoid organs. LYMPH NODE:Major functions of lymph nodes are 1. Acts as a physical and biological filter. Filters bacteria, viruses or foreign macromolecules. 2. Proliferating B cells undergo affinity maturation in which B cells respond to antigen 3. Mature B lymphocytes, macrophages, follicular dendritic cells are found lymph nodes SPLEEN:Major functions of spleen are 1. Spleen serves as a critical line of defense against blood –borne pathogens 2. Splenic macrophages also have important function of recognizing and eliminating any abnormal, damaged cells (RBC, WBC, etc) from blood.

11.What is the Lymphocyte Traffic? and concise answer their major function please. The restless migration of lymphocytes among organs is called as lymphocytes traffic. Major functions:1. As lymphocytes travel from organ to organ, they can survey the entire body foci of infections or foreign antigens. 2. Help maintaining a balanced overall distribution of lymphocytes among tissues. 3. As migrating lymphocytes are forced to compete with one another for the limited space available in each tissue (creates a pressure on population). NOTE:: Blood lymphocytes most commonly enter tissues by passing through the walls of specialized blood vessels known as high endothelial venules (HEVs)

12.Concise answer the challenges of the immune system please. Main challenges faced by the immune system are:1. System must be able to recognize an infinite variety of foreign substances. 2. Immune system must initiate the appropriate response against each invaders 3. System must shut off when finished. 4. Distinguish between infectious and non-infectious cells. 5. Must avoid responding to self (auto immunity)

13.Please summarize the specificity of antigens. All immunogens encountered in nature including pathogens are t type of molecules and not all of them are antigens. • The specific set of chemical features that are recognized by given antibody or TCR is called Epitope. • an epitope is the specific site to which a particular immunoglobulin or TCR binds • Not all antigens or epitopes are immunogenic. • T-cells recognize their epitopes in association with MHC. • On the basis of Shape epitopes are classified as Linear & Conformational epitopes. • T-cell epitopes not only serve as a cytotoxic T cell responses but are also essential for nearly all B-cells response. • a molecule must contain at least one T-cells epitope to be immunogenic • molecules with only B-cells epitopes may serve as targets for antibodies.

14.Please summarize the mechanisms of immune tolerance. The immune tolerance can be further classified as Central and peripheral tolerance. The principle mechanism of lymphocytes tolerance are: Deletion:- Apoptotic cell death  Energy:- Function inactivation without cell death  Suppression of effector lymphocyte activation and effector functions by regulatory lymphocytes. Central tolerance is mainly due to deletion, whereas rest of three contribute in Peripheral tolerance

Central Tolerance:Self tolerance may be induced in generation lymphoid organs as consequence of immature selfreactive lymphocytes recognizing antigen this is called Central tolerance Peripheral Tolerance:In peripheral sites as a result of mature self reactive lymphocytes encountering self-antigen under particular condition is called peripheral tolerance

15. Summarize the mechanisms Type I ~IV hypersensitivity please.

CLINICAL MANIFESTATION

MECHANISM

TYPE I

TYPE II

TYPE III

TYPE IV

IgE-Mediated Hypersensitivity

IgG-Mediated Cytotoxic Hypersensitivity

Immune Complex-Mediated Hypersensitivity

Cell-Mediated Hypersensitivity

Ag induces crosslinking of IgE bound to mast cells & basophils with release of vasoactive mediators.

Ab directed against cell surface antigens mediates cell destruction via cell complement activation or ADCC

AgAb complexes deposited in various tissues induce complement activation and an ensuing inflammatory response mediated by massive infiltration of neutrophils.

Sensitized TDTH cells release cytokines that activate macrophages or TC cells which mediate direct cellular damage.

Systemic anaphylaxis & localized anaphylasis such as hay fever, asthma, hives, food allegergies and eczema.

Blood transfusion reaction, erythroblastosis fetalis & autoimmune hemolytic anemia.

Localized Arthus reaction & generalized reactions such as serum sickness, necrotizing vasculitis, glomerulonephritis, rheumatoid arthritis, & systemic lupus erythematosus

Contact dermatitis, tubular lesions & graft rejection.

16.How do NK cells recognize and kill the sensitive target cells? RECOGNITION  NK “missing self” recognition of cells that lose MHC class I expression.  NK “stress” recognition of cells that express molecules without on normal cells.  NK cells can recognize target Fc receptors  Missing self recognition is based on the presence of both inhibitory and activating receptors on NK cells. 15

 Surface markers identifying as human NK cells; TCR- , mIg-, CD56+, CD16+ KILLING  NK cells looks like Large Lymphocytes and contains granules.  They are ready to kill target cells without clone expansion  They kill target cells using perforin.  They can rapidly produce cytokines upon ligand recognition.  They seem to be especially important in resistance to intracellular infections of viruses or bacteria. OR NK cells recognize the target cells with the CD16Fc receptors binding to them with the help of chemical substances called perforius , these are secretions from NK cells , they will kill the target cells.

17.How do the Neutrophil or Monocyte emigrate from blood to the focus of injure or infection? Emigration of neutrophil include 4 steps:As an inflammatory response develops ,the vascular endothelium is then said to be activated or inflamed. In the: First step, neutrophils attach loosely to the endothelium by a low affinity selection carbohydrate interaction  Second step:- Activation mediated by chemoattracts, as neutrophil rolls, it is activated by various chemoattractants  Third Step:- Attachment mediated by integrins, Activating signal(mediated by G-proteins) induces a conformational change in the integrin molecules in the neutrophil membrane, increasing their affinity for the Ig-Superfamily adhesion molecules on Endothelium  Last Step:- Subsequently, neutrophils migrate through the vessel walls into the tissue

18. Please Summarize three major pathways of Neutrophil or Macrophage for engulfing extracellular materials or pathogens. Three Major path way are 1.Pinocytosis :: Unmodified fluid 2.Receptor-mediated endocytosis :: Modified fluid & particle 3.Phagocytosis :: Particle usually > 100nm in diameter PINOCYTOSIS:Occurs through formation of minute surface vesicles filled with unmodified extracellular fluid RECEPTOR-MEDIATED:Is triggered by the binding of a soluble ligand to one or more specific surface receptors, the resulting polymerization of clathrin protein on the cytoplasmic aspect of the plasma membrane leads to invagination of the receptor and formation of coated pit.

PHAGOCYTOSIS:Occurs when multiple surface receptors sequentially engage the surface of a target particle, usually >100nm in diameter. Phagosomes are lined by sing lipid bilayer derived from the plasma membrane

19. Please summarize the major surface proteins and their functions of T lymphocytes. The T cell do not “see” soluble antigens, but rather recognize antigen bound to specialized molecules on the surface of their cells. Most T cells respond to protein antigens. Common Receptors or surface proteins are. TCR(T-cell receptor):There are two types of TCR: α/β and γ/δ TCR-CD3 complex: The CDR3 loops with greatest sequence diversity recognize the T cell contact residue of peptide. >>Structure basis for generating the specificity of recognition of T cell to antigen >> CDR1/2 loops recognize a –helix-polymorphic residue. CD4 & CD8 Co-receptors:The expression of CD4 & CD8 divides mature T-cells into two mutually subsets those that recognize antigen in the context of class II MHC molecules(CD4 cells) and those recognized antigen bound to class I molecules (CD8 cells) Co-stimulator molecules:T-cells activates the delivery of both TCR signals and a second set of signals generated by costimulatory molecules. >> In absence of a proper co-stimulus ,stimulation Of TCR alone cannot induce activations of tcells but energy of T cells >>Best characterized co-stimulatory molecule is CD28. >>CD28 binds to 2 distinct surface molecules B7.1 and B7.2

20. Please summarize the major surface proteins and their functions of B lymphocytes. BCR-Complex:SIgM/SIgD abd Tga/IgB BCR recognizes binds to antigen epitope on the surface of antigen but cannot itself generate a signal as TCr does. >>Cross lining or more BCrs by a bivalent or multivalent antigen brings together several of two Igα & Igβ cytoplasm domin with their IATH. Cytokine Receptors:B-cells express various kinds of cytokines receptors on their surface such as IL-1R, IL-2R,IL-4R, IL-5R,ETC Binding of cytokines to antigen stimulated B-cells induce activation & proliferation of B-cells. Complement Receptors:IgM and CD 21 are cross linked by antigens that has activated complement . Cd 21 is phospho-related and act as receptor. Ligation of co-receptors increases B-cell receptor signaling 1000-10,000 folds

Fc Receptors:The majority of B cells express IgG Fc receptor II that binds only complex or polymeric IgG,aiding the B-cells in capturing and binding og antigens Other surface markers include, Mitogen receptors, mHC Antigens & CD Antigens

21. Please summarize the major subsets and their functions of T lymphocytes. T cell population is heterogeneous with respect to both functional capabilities and cell surface phenotypes::  On the basis of ACTIVATION STAGE 1) NATIVE/RESTING T CELL 2) EFFECTOR T CELL/ACTIVATED T CELL 3) MEMORY CELL  On the basis of CELL SURFACE PHENOTYPES 1) ΑβT CELL/ T CELL 2) CD4 T CELL/ CD8T CELL  On the basis of FUNCTION CAPABILITIES 1) HELPER T CELLS :: promotes cell mediated & antibody response 2) CYTOTOXIC T LYMPHOCYTES :: kill antigen-bearing Target cells. 3) REGULATORY T CELLS ::  regulatory cell mediated & antibody response Helper T cells:Helper T cells are further classified as TH1 & TH2 Cells TH1 cells produce IL-2 ,IFN- γ and TNF B >>when activated helper T cells produces soluble lymphokines that can regulate activation of T cells, B cells, macrophages and other cells TH2 cells promote neutralizing IgG antibodies mast cell degranulation, eosinophil activation and suppression of macrophage activation. Cytotoxic T lymphocytes:These cells are usually CD8 And recognize antigen in context of MHC class I molecules. Functions:Play a prominent role in host defense against viral, infections, bacterial pathogens and play in immune surveillance against malignancy. Memory T cells:The memory T cells are prompter of more effective immune response to an antigen when it is attacks second time. Regulatory t-cells:T-cells play a central role in the regulating both the humoral (antibody) and cell mediated arms of immune system.

22.Please summarize the major subsets and their functions of B lymphocytes. B1 and B2 cells are the two major subsets of B lymphocytes. B1 cells CD5 + SmIgM High levels SmIgD Little

B2cells + +

Functions of conventional B2 cells: Responsible for humoral immunity : B lymphocytes can function as APCs, by processing and displaying foreign substances in a MHC-binding manner that can be recognized by T-lymphocytes  Immune Reduction:Activated B cells can secrete certain cytokines that influence the growth and activities of other immunologically important cells.

23. Which components involve in innate immune response? The components that can be considered as part of Innate response are Anatomic: Skins(epidermis/dermis)prevents infectious agents from entering tissue beneath  Sebum/sweat(lactic & fatty acid) maintain acidic pH(prevent colonization of bacteria etc)  Mucous on delicate lining of respiratory & digestive system.  Fluid flow(such as tears, gastric fluid, saliva),cough, sneeze, antimicrobial peptides in skin, local cytokines and chemokines. Immune cells: Phagocytes  NK cells  γδ T cells  B1 cells  NKT Humoral proteins:• Complements • Peptide antibodies • Acute phase response • Antimicrobial enzyme and Binding Proteins

24. What are the double signals for T cells activation Naïve CD4+T cells requires two distinct sets of extracellular signals to induce their proliferation and differentiation into effector cells. 

First signal is the recognition of Peptide-MHC complexes by the TCR and it provides specificity to the subsequent T cells response.



Second signal for T cells activation is provided by the molecules on the APCs, which are called Co-stimulators. o In absence of co-stimulation, T cells that encounter antigen either fail to respond and die by apoptosis to enter state of unresponsiveness called anergy

o CD28 is the best characterized costimulatory molecule. o The combination of TCR stimulation and interaction of CD28 with its B7 ligands fully activates T cells and result in greater Lymphokines production.

25. What are the differences of primary and secondary response for antibody production? PROPERTY RESPONDING B-CELL LAG PERIOD FOLLOWING ANTIGEN ADMINISTRATION TIME OF PEAK RESPONSE MAGNITUDE OF PEAK ANTIBODY RESPONSE ISOTYPE PRODUCED ANTIGENS ANTIBODY AFFINITY

PRIMARY RESPONSE NaÃ¯ve(virgin)B cells Generally 4-7 days

SECONDARY RESPONSE Memory B cells Generally 1-3 days

7-10 days Varies depending on antigen IgM predominate (early in response) Thymus-dependent and thymus independent Lower

3-5 days Generally 100-1000 times higher primary response IgG Predominates Thymus dependent Higher

26. Please describe the exogenous pathway for antigen presentation. Exogenous antigens  peptide/MHC class II complexes  CD4+ T cell [phagocytosis, endocytosis, pinocytosis]

27. Please Describe the Active and suppressing receptors on the surface of T cells, B cell and NK cells. T CELL:

B CELL:

NK:

TCR-CD3 complex CD28 CTLA-4 BCR complex CD40 FcγRII-B KAR KIR CD94/NKG2A

peptide/MHC complex B7.1 B7.2 conformational determinants of antigen CD40L Fc fragment of IgG glycoprotein MHC class I molecules HLA-E OR

NK cells have two types of surface receptors. 1. NKR-P1:- Triggers killing By NK cells 2. Ly-49:-Prevents activation of NK cells T cells:1. The combination of TCR stimulation & the interaction of CD28 with its B7 ligand fully activates T cells 2. CTLA-4 is suppressing receptor on T cells. B-cells:1. B cells express various kinds of Cytokines receptors on their surface , such as IL-R1, ILR2, IL-R4 etc, binding of B-cells with its cytokines activates B-cells. 2. B-cell activation is suppressed by binding of Antigen antibody complexes to B-cell surface:-FC-8RIIB(CD32). This is a negative feedback mechanism.

28. Please describe the process of B cell- mediated immune response. B-cell response to T cell dependent antigen TI-1 ANTIGEN  Most TI-1 antigens are polyclonal B-cell activators (mitogens) that is, they are able to activate B cells regardless of their antigenic specificity.  At high concentration, some TI-1 antigens will stimulates proliferation and antibody secretion by as many as 1/3th B cells.  At low concentration of IT-1 antigens, only those B cells specific for epitopes of the antigen will be activated. TI-2 ANTIGEN  Activate B cells by extensively crosslinking the IgM receptor.  They are not B-cell mitogens and so do not act as polyclonal activators.  TI-1 antigens will activate both mature and immature B cells, but TI-2 antigens activate mature B cells and inactivate immature B cells.  Although the B cell response to IT-2 antigens doesn’t require direct involvement of T cells. Cytokines derived from T-cells are required for efficient B cell proliferation and for class switching to isotype other than IgM.

29. Please demonstrate the basic structure of immunoglobulin. • • • • • •

Every Ig molecules Is made up of two different types of polypeptides. The larger heavy(H) chain and the smaller light(L) chain. The H chain are twice as large L chain. Number of H chain & L chain is equal General formula is (H2L2)n The chain are held together non-covalent forces & covalent di-sulphide bridges.

• • •

Usually a bilaterally symmetrical structure 100-110 AA in a globular domain of H & L chains All normal Ig confirm to this basic structure.

30. Please describe the biological activities of Igs. Igs are bi-functional molecules that bind antigens and in addition other biologic processes that are independent of anti body specificity. These activities are localized to a particular par of the protein 1-Antigen binding (To the combined VH and VL domains) 2- Other activities (CH domains ) Some other activities include o Activities of Variable Region: >>Binding is non-covalent and involves weak forces of attractions. >>Antibodies can produce resistance to infection by opsonizing the organisms >>Antibodies can bind to viruses and reduce their ability to invade host cells. o Activities of Constant region:>>Although Ab binding, blocks the attachment of toxins and Viruses (Neutralization), antibodies can’t alone directly destroy Ag. >> Many effector functions are triggered by binding of antigens to the spatially distinct combining site in V regions o Complemnet Fixation:>>ability of antibody to protect against infection is in many instances, greatly enhanced by the complement system o Opsoniztion:IgG is an opsonizing antibody. It reacts with epitopes on microorganisms via its Fab regions but it is Fc region that confers the opsonizing property. o Antibody –dependent Cell mediated Cytotoxity:-

>>NK cells also recognize antibody coated target cells by their FcγRIII , NK cells kill target cells that are coated with antibody molecules. This process is called ADCC

31. Please describe what are the C3 convertases for the three kinds of activating complement pathways? C3-convertase in 3 kinds of pathway CLASSICAL PATHWAY & LECTIN PATHWAY:-C3 convertase: C4b2a Cleavage of C3 produce two fragments: • C3b---larger, continues the sequential activation of successive components • C3a---smaller, fluid-phase, anaphylatoxin ALTERNATIVE PATHWAY:- C3 convertase: C3bBb o C3bBb is alternative pathway C3 convertase. o The convertase in turn can bind and cleave an additional molecule of C3 to form a layer complex (C3bBb3b) that C5 convertase activity. o The alternative pathway c3 convertase (C3bBb) is extremely unstable & would ordinarily dissociate rapidly.

32. Please describe what are the C5 convertases for the three kinds of activating complement pathways? CLASSICAL PATHWAY:C4b2a3b: Classical pathway C5 convertase Cleavage of C5 produces two fragments: • C5b---binds to the cell surface, nucleus for binding the terminal complement components • C5a---released into the fluid phase, most potent anaphylatoxin and chemotactic factor LECTIN PATHWAY & ALTERNATIVE PATHWAY:Lectin Pathway:-C5 cnvertase:C4b2a3b Alternative Pathway:-C5 convertase: C3bBb3b The late phase compliment cascade begins when C5 is bound & then Cleaved by convertase of classical, MBL or alternative pathway into C5a & C5b.

33. What are the primary and the secondary signal of T cell activation? Naïve CD4+T cells requires two distinct sets of extracellular signals to induce their proliferation and differentiation into effector cells. o First signal is the recognition of Peptide-MHC complexes by the TCR and it provides specificity to the subsequent T cells response. o Second signal for T cells activation is provided by the molecules on the APCs, which are called Costimulators. o In absence of costimulation, T cells that encounter antigen either fail to respond and die by apoptosis to enter state of unresponsiveness called anergy o CD28 is the best characterized costimulatory molecule.

o The combination of TCR stimulation and interaction of CD28 with its B7 ligands fully activates T cells and result in greater Lymphokines production.

34. How do activated B cells undergo ‘affinity maturation’?  Affinity maturation is the phenomenon by which B cells produce antibodies with increased affinity for antigen during the course of an immune response, esp. the antibody produced in secondary response tends to be higher affinity than that in primary response.  This is thought to be the basis for selecting cells that produce high affinity immunoglobulin: Cells with higher affinity Immunoglobulins not only are stimulated more strongly through their BCRs, but also compete more effectively in internalizing antigen and presenting it to local TH cells. In other words antigen selects the B cells with higher affinity BCR to proliferate and complete clonal expansion. Together, these selective process likely account for the antibody affinity maturation.

35. What are the three phages of immune response? 1) Recognition 2) Activation 3) Proliferation

36. What are the function of primary immune organs ? Bone marrow and thymus are considered as the primary Immune organs and there function is usually the production of T & B lymohocytes. Bone marrow::T & B lineade cells both arise from a subset of hematopoietic stem cells(HSC) in the bone marrow. Hman B lymphocytes development takes place entirely within the bone marrow.

Thymus:Thymus consists of thymic stromal cells(TSC) and thymocytes . T cells develop from immature precursors that leave marrow travel through the blood stream to the Thymus.

37. What is the clonal selection theory? In 1957, Burnet enunciated the clonal selection theory, The clonal selection theory has been further refined and is now accepted as the underlying paradigm of modern immunology According to the theory 1. Individual lymphocyte expresses membrane receptors that are specific for a distinct Ag. This unique receptor specificity is determined before the lymphocyte is exposed to the Ag. 2. Binding of Ag to its specific receptor activates the cell, causing it to proliferate into a clone of cells that have the same immunologic specificity as that of the parent cells. 3. Lymphocytes with receptors against self are deleted from an early stage or became forbid clone and are absent from the repertoire of mature lymphocytes.

During development progenitor cells give rise to large numbers of lymphocytes, each with a different specificity

Pool of circulating small lymphocytes

Proliferation & differentiation of pathogen- activated lymphocytes to form a clone of effector cells

38. How to understand the autoimmunity?  Autoimmunity is defined as an acquired immune reactivity against self antigens.  This response usually produces autoantibodies and autoreactive T cells.  The immune system has the capacity to mount an immune response to virtually all molecules /cells.  Autoimmunity usually results from a failure or breakdown of the mechanisms normally responsible for maintaining self tolerance in B-Cells, T-cells or both.  When an autoimmune responses damage the tissues autoimmune disease occurs.  Prominent examples include Coeliac disease, diabetes mellitus type1 (IDDM), systemic lupus erythematosus (SLE), Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis (RA) etc.

IMMUNOLOGY PG QUESTION PAPER 2015 TERMS 2. 3. 4. 5. 6. 7. 8. 9. 10.

CANCER STEM CELLS NEGATIVE â&#x20AC;&#x201C;SELECTION OF THYMOCYTES SERUM SICKNESS ADCC IMMUNOLOGIC SYNAPSE CLUSTER OF DIFFERENTIATION AICD PATTERN-RECOGNITION RECEPTORS (PRRS) IL-2

QUESTIONS 1. WHAT IS THE ROLE OF IMMUNE SYSTEM? (8 POINTS) 2. WHAT IS THE COLONIAL SELECTION THEORY? (10 POINTS) 3. WHAT ARE THE DIFFERENCES OF PRIMARY AND SECONDARY RESPONSE FOR ANTIBODY PRODUCTION (8 POINTS) 4. PLEASE DESCRIBE WHAT ARE THE C5 CONVERTASES FOR THE THREE KINDS OF ACTIVATING COMPLEMENT PATHWAYS (6 PONTS) 5. PLEASE DESCRIBE THE ACTIVE AND SUPPRESSING RECEPTORS ON THE SURFACE OF T CELL, NK CELL & B.CELL. (10 POINTS) 6. PLEASE DESCRIBE THE EXOGENOUS PATHWAY FOR ANTIGEN PRESENTATION. (8 POINTS) 7. PLEASE SUMMARIZE THE MAJOR SUBSETS AND FUNCTIONS OF T LYMPHOCYTES. 8. SUMMARIZE THE MECHANISMS TYPE I HYPERSENSITIVITY PLEASE (10 POINTS)

ANSWERS TERMS 2. CANCER STEM CELLS

Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample.

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