General PathologyLecture/4

Immunity &Hypersensitivity

ByAssociate Professor

Dr. Wadhah Mahdi Al-Badir

• Allergen: An antigen that has the capability of inducing IgE rather than IgG or A production in an individual, resulting in an allergic response.

• Allergy: A largely IgE-mediated, inflammatory response to non-pathogenic antigens resulting in pathological changes that may be damaging to the

host.• Allogeneic: Term referring to genetically different members of the same

species.• Allograft: A tissue graft between two members of the same species who

are not genetically identical• Atopy: Usually used synonymously with allergy. It is used to describe IgE

mediated hypersensitivity responses.• Autograft: Transplantation of tissue from one area to another on the same• individual.• Autoimmunity: An immune response to self antigens which may be

confined to a particular tissue or may be expressed systemically or throughout the body. Such a response may have a range of pathological effects resulting in autoimmune disease.

• Accessory cell: Term used for a cell (often an antigen presenting cell), which plays a B lymphocyte (B cell): Mature products of the lymphoid progenitor cell that

• when stimulated by antigen may proliferate and differentiate into memory cellsvital role in a specific immune response but cannot by itself mediate the same

Antibody-dependent cellular cytotoxicity (ADCC): Cells expressing foreignantigen (e.g. viral antigens) become the target of antigen-specific antibodies.These antibody-labelled target cells may then be destroyed by specialised killercells (including some large granular lymphocytes and macrophages) which havereceptors for the Fc part of the antibody (Fc receptors, FcR) and bind to thetarget cell.Antigen-presenting cell (APC): Cells that express molecules coded for by theClass II genes of the major histocompatibility complex (MHC). They arecapable of processing and presenting antigen to T cells. APC include dendriticcells, macrophages and B lymphocytesB lymphocyte (B cell): Mature products of the lymphoid progenitor cell thatwhen stimulated by antigen may proliferate and differentiate into memory cells or terminally differentiated plasma cells, which secrete antibody of the samespecificity as that on the originally activated parent cell.

Table /Characteristics that distinguish T from B lymphocytes

B cells Tcells Characteristic

Mononuclearleukocyte/lymphocyte

Mononuclearleukocyte/lymphocyte

Cell type

Immunoglobulin/CD79a/bB cell antigen receptor (BCR)

Tcell antigen receptor(TCR)/CD3

Membrane molecules thatAllow binding of antigen^ the antigen receptor

Membrane Immunoglobulins(mIg), CD19, CD20, CD40

CD3, CD4 or CD8 Characteristic surfaceMembrane molecules

Antibodies Lymphokines Chief secretory products

CELLS AND TISSUES OF THE IMMUNE SYSTEM 3Figure 1.1 Representation of the developmental lineage of immunologically active cells

Figure 1.4 Antibody-dependent cellular cytotoxicityIn a virally infected cell, some of the viral proteins are expressed on the cell membrane allowingvirus-specific antibodies to bind to them. A killer cell can attach to this antibody using its Fcreceptor and is thereby activated and kills the virally infected target cell. This activity is known asantibody-dependent cellular cytotoxicity (ADCC).

• Antigenic determinant: That part of an antigen which binds to antigen-binding sites on the T or B cell antigen receptors. Also known as an epitope. Complex antigens may have many different antigenic determinants or epitopes, each of which can be recognised by different T or B cells.

• Antigen processing: The pathways (endogenous or exogenous) by which largemolecules are broken down within antigen presenting cells so that they can associate

with the products of the major histocompatibility complex genes and be presented on the surface of the antigen-presenting cell.

• Carrier: A large molecule, which when attached to a smaller, non-immunogenicmolecule (hapten) allows the latter to stimulate an immune response.• Cell-mediated cytotoxicity: The killing of another cell by an effector cell (e.g.cytotoxic T cell, natural killer cell, macrophage).• Cell-mediated immunity (CMI): All those immune responses in which antibodyplays little or no part. Largely mediated by T cells, macrophages and NK cells.• Chemotaxin: A chemical capable of attracting cells through binding of specificreceptors on the cell surface and promoting their chemotaxis.• Chemotaxis: The directed migration of cells up a concentration gradient of an

Inflammation versus Infection/ protection x invasion• Inflammations either A. acute, B. chronic• Changes in acute inflammation include 1.vascular events (hemodynamic& inc permeability) 2.cellular events (leukocytes exudates& phagocytosis)

• Components of immune system 1. Innate, natural immunity. Non specific, No Ag specificity A).humoral ; complement system. B). cellular; by PMNs, Macrophages, natural killer cells, NK 2. Adaptive immunity , specific.; Ag specific A).humoral; Ab formed by B lymphocytes B). cellular mediated by T lymphocytes forming cytokines

• Lymphocytes appear morphologically homogenous group, but functionally are of 2 major types B.-lymphocytes which differentiate into plasma cells Abs production

& T- lymphocytes proliferate in contact with appropriate Ag, after that accessory cells (PMNs&macrophages) play critical role in completion of the immunological reaction. These 2 types can be only differentiated by immunological methods,B cells by specific Ab secretion, T cells by surface molecule, monoclonal Ab according to cluster differen –tiation(CD)

Macrophages are monocytes & tissues macrophages;Their functions are:

1. Ag recognition & presentation to B &T lymphocytes2. Phagocytic action due to presence of surface receptor for Fc fragment of IgG&C3

complement3. IL-1 production play a role in B&T cells differentiation.4. Lysing action on tumor cells by toxic metabolites.5. As effector cells in cell mediated immunity e.g. delayed hypersensitivity reaction.Act as mediator of inflammation in release ot PGs ,,activation of coagulation factors&

in secretion of acute phase reactant proteins by the liver• ------------------------------------------------------------------------------------------------------- • Human Leucocyte Antigen(HLA) System It is not a component of Immunity system, but regulate it& play role in tissue matching

and transplantation, most transplantation genes are present in ch.6of all nucleated cells of the body& platelets called Major Histocompatability Complex(MHC) or (HLA) complex on loci A,B,C&D on P arm of ch 6 w marked variation in allelic gene in each locus,so it is highly polymorphic

MHC divided into1.Class I MHC Ag have loci as HLA A,B&C. CD8 lymphocytes carry receptor for Class I

HLA Ag and used to identify it

MHC

2. Class II MHC Ag has single locus HLA D w further 3 loci DR.DQ,DP..It is identified byB cells&CD4+T or T helper cells.

3.ClassIII Ag: some component of complement system C2,C4.codedon HLA complex Ag ,it doesn't associate w HLA expression(useless in T matching).The polymorphism of Class I&II by numbered loci eg.HLA-A1,A2..etc.

Roles of HLA complex in1) Organ transplantation 2)regulation of immune system, humoral & cellular immunityA) I Ag regulates function of cytotoxic cells (CD8+} eg. Viral infection.B) II Ag regulates function of helper T cells(CD 4)3)Association of disease w HLA

a. inflam..ankylosing spondylitisb. Autoimmune dis..Rheumatoid arthritis.c. Inherited disorders of metabolism..idiopathic hemochromatosis0000000000000000000000000000000000000000000000000000000000000000000

Diseases of ImmunityImmunity = Resistance to protect the bodyHypersensitivity is interchangeable w allergyDiseases of immunity are of 4 types

Diseases of Immunity1. Immunodeficiency disorders: Primary ,or Secondary eg.AIDS.2. Hypersensitivity Reactions an exagurated immune response leading to various types

of T injury.3. Autoimmune diseases: failure to recognize self from non self( collagen diseases)4. Possible immunity disorders: may be due to immunological disorder in their

etiopathogenesis eg. Amyloidosis.Primary Immunodeficiency1. Combined B & T cells and Igs (bone marrow disorders)2. T cells defects, Thymic hypoplasia.3. B cells defects, Ab deficiency diseases.4. Common variable immunodeficiency,decrease Ab production.Secondary immunodeficiency5. Infections 2.cancer 3.lymphoid diseases 4.Malnutrition 5.sarcoidosis 6.Autoimmune disease 7.transplantationAIDS /Acquired Immunodeficiency Syndrome,A human T cell leukemia-lymphoma virus,a s cytopathic virus has tropism to CD4 T

lymphocytes causing lysis of cells..it is of two types HIV1&HIV2.the viron consists of core protein p24&p18,2 strands of RNA & the enz. reverse transcriptase

AIDS

WHO definition: existence of at least 2 major signs w at least one minor signMajor signs: 1)wht loss >10% of body wht, 2) ch. diarrhea >1m, 3)fever >1m.Minor signs: 1) rec orapharyngeal candidiasis 2)persistant generalized

lymphadenopathy 3) persistent cough >1mMode of transmission; 1)sexual 75% 2) paranteral 25% 3) perinatal transmissionVirus isolated from; semen vaginal ,cervical secretion, breast milk, synovial ,pericardial

peritoneal and amniotic fluidAIDS cannot transmitted by non sexual casual contact, or sharing household facilities.Sterilization & disinfection: by usual chemical germicidal w low conc. As formaldehyde

5% , ethanol 70%,chlorine bleaching,gluteraldehyde2%.Phases of AIDS are three1. Acute HIV syndrome (3—12w) seroconversion illness.a)viremia (high level) b)seroconversion in3-6 w(virus specific imm response),c) inc.CD8+T cells, d) selflimited nonspecific viral infection(flue like).2.Middle chronic phase (10—12 yr)competition bet HIV & immune systema) Viremia b) ch stage ,duration depends on host imm syst, c) CD4+ T cells continue to

prolif but the end result is dec.in No ofCD4+T,d) CD8+T cell count remain high,f) Clinically a stage of latency,(CDC stage II) or w constitutional sympt+persistant

gen.lymph (CDC stageIII)

AIDS. cont.3)Final stage characterized by profound immunosuppression& onset of full-blownAIDS w

the following features a) marked inc in viremia,b) time fom inf to eull blown stage is 7—10 yrs death.c)CD4+T cell count dec.(<200/ul),d)clinically the features of 5 subgroups (CDC stage IV)

1.subgr.A constit sympt of fever>1m,wht loss>10% B Wht, ch diarrhea >1m.2.Subgr B neurogenic disease( vir meningoencephalitis’aseptic meningitis,periph

neuropathy& AIDS dementia.3. Subgr C secondary opportunistic inf.(viral,bact & fungal or parasitic)4.Subgr D s econdary neoplasm; (Kaposi sar, HL&NHL,Burkitt lymphoblastoma,, prim CNS

lymphomas)5. Subgr E: CD4+T cells<200 ,pul TB,& rec pneumonia.Average survival at onset of stage 3=18—24 m.PATHOLIGICAL CHANGES: morphological changes are stage dependent1.Lymphoid tissues early,B cells hyperplasia(nonsp follicular hyperpl+ plaslacytosis in

medulla of LNFull blown AIDS;universal lymphoid depletionappor inf&malig lymphoma2.Wide spread apport inf3.AIDs associated cancer,uterus vagina cervix anus4.Neurological manifestations5.AIDS nephropathy,segmental glomerulonephritis.

LAB DIAGNOSIS

1. initial testing forAb HIV by ELISA2. Confirmation by Western blot OR immunofluorescent test.of 2 types1) specific test, i.serologicaltest ELISA,Western blot,& immunofl.Ii Ag detection tests using envelope&core pt of HIV by recombent DNA

techniqueIii.Virus isolation in cultureiv.Polymerasr chain reaction PCR2)indirect tests ; iCD4&CD8 cells count,reversal CD4/CD8 ratioii.Lymphopenia iiiLN biopsy iv thrombocytopenia Vincrease

B2microglobulin.

AUTOIMMUNE DIDEASES

EXAMPLESi.Systemic anaphylaxis (antisera,drugs,sting)ii.Local anphylaxis(hay fever, br asthma,food allergy)i.Autoim hemolytic an,ITP, trasf reaction, eryth fetalis, leucopenia, drug inducedii. Mysth gravis, male sterilityiii. Tumor cells,parasites

i.ATS inj,farmer’s lungii.Glomerioneph, collagen dis, sk dis,uveitis

Type IV I. Clasical delayed hypersensitivity i.tuberculin,TB,Tb leprosy,

(Cell mediated) mediated by CD4 + t lymphocytes typhoid, contact dermatitis

II.T cell mediated cytotoxicity by CD8+ ii virus infected cells,tumor T cells cell,transplant rejection

Autoimmune Diseases

Immune system fail to distinguish between self & non self,it is the opposite of immune tolerance

immune tolerance is a normal phenomenon since fetal life, it is the ability to recognizeSelf tissue antigens, Through1. Clonal elimination of T lymphocytes