adaptive immunity

goal of adaptive immunity

 maintain homeostasis by protecting the body from pathogens, foreign molecules, and harmful toxins

does adaptive immunity always do good?

no- sometimes more harm than good

lines of defense

• first line: physical barriers

• second line: innate immune system

• third line: adaptive immune system

first line of defense

• physical barriers of the skin and mucus membranes as well as other intrinsic barriers

• intrinsic: mechanical, chemical, microbiological barriers

mechanical barriers

• Expulsive forces (coughing, sneezing, defecation and urination) help to rid the body of pathogens before they can attach to and breach the mucus membranes)

• Ciliary beating helps sweep pathogens from upper and lower airway

• Tight junctions in epithelium prevent pathogens from slipping between cells to enter underlying host tissue

chemical barriers

• Low pH (stomach, vaginal fluids and sebaceous fatty acids) prevent pathogenic bacterial colonization

• Proteolytic enzymes (lysozymes, pepsin in gut) break down pathogenic components

microbiological barriers

• Commensal flora compete with pathogens for resources (space and nutrients)

innate immune system

• use of surface receptors on phagocytic cells that recognize evolutionary conserved patterns unique to pathogens (ex. LPS- lipopolysaccharide, a sugary lipid found in outer cell wall of gram -ve bacteria)

cells and components in innate immune system

• phagocytes

• NK cells

• inflammation

• antimicrobial proteins

• fever

phagocytes

• Mainly consist of tissue resident and “wandering” macrophages

• Ingested pathogens occupy phagosome then fuses with lysosome to produce a phagolysome where digestion of pathogen occurs

NK cells

• Do not phagocytose pathogens

• Secrete toxic chemicals or induce apoptosis in target cells

antimicrobial proteins

interferons and compliment

interferons

• released by infected cells to help prevent infection of neighboring cells by inducing neighboring cells to produce anti viral proteins that block protein synthesis and degrade viral RNA

compliment proteins

• help enhance inflammation, promote phagocytosis, and cause cell lysis (membrane attack complex)

fever

• Systemic result of infection

• Initiated by release of pyrogens which include bacterial toxins and/or components. Antigen-antibody complexes or substances released by phagocytes

• pyro= fire

adaptive immunity

• eliminates pathogens that may have circumvented or overwhelmed the first two lines of defence and to confer protection from new and emergent strains of pathogens

2 streams of adaptive immunity

cellular and humoral

cellular response

involve targeting killing of infected or abnormal cells

humoral response

involve production fo soluble immunoglobins (antibodies) that confer protection from specific pathogens through variety of effector functions

adaptive immunity characteristics

specificity (self vs non self) and memory

specificity

• The ability to mount a response to a particular pathogen or foreign substance while being able to discriminate between self vs non self antigens

consequences of specificity

B cell may only be able to mount a response to one particular strain of pathogen without recognizing any of a number of closely related pathogens

memory

ability to recall exposures to specific pathogens and provides the adaptive immune system with the ability to mount an even stronger response to a pathogen upon repeat exposure

how to vaccines work

memory component of adaptive immunity

how does the magnitude of the adaptive immune response change with exposure

innate vs adaptive specificity

innate: broad specificity

• Recognize broadly conserved PAMPs (pathogen associated molecular patterns)

• PAMP location: on structures that are essential for pathogen survival and accessible to host pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) which are present on phagocytes

• TLRs recognize PAMPs that are common to broad classes of organisms (ex. TLR-4 recognizes LPS which is a component of the outer cell wall of all gram -ve bacteria)

adaptive: narrow specificity

• Both B-cell and T-cell receptors recognize very specific antigenic determinants (8-10 amino acids) that may be specific for only one particular strain of pathogen

• These antigenic determinants can be any protein on the pathogen and may not be essential for pathogen survival

innate vs adaptive repertoire

innate: limited repertoire

• PRRs are encoded in the host germ line DNA, limiting absolute number of PAMPs for which PRRs are produced

• If pathogens modify their PAMPs then the host PRRs will not mount a response

adaptive: vast repertoire

• B and T cell receptors which recognize antigenic determinants are produced through somatic recombination (mixing, matching, and recombing) of host gene segments, resulting in the generation of T cell and B cell receptors that can detect virtually any antigenic determinant

innate vs adaptive response

innate: immediate response

• Components are preformed

• Response may include increased phagocytosis, complement activation and inflammation

adaptive: slow response

• Response is initiated by antigen presenting cells (APCs) which travel from site of infection to nearby lymph node where immunocompetent cells of the adaptive immune system reside

• Process involves antigen presentation, differentiation and clonal expansion of T cell and/or B cell resulting in a cellular or humoral response

• 3-5 days to initiate

innate vs adaptive memory

innate: lacks memory

• Responds in same way each time

adaptive: memory

• Memory cells ensure a large reservoir of differentiated cells ready to tackle infection of previously encountered pathogens

where is initiation of an adaptive response

secondary lymphoid tissues:

• spleen

• MALT

• lymph nodes

spleen as origin of adaptive response

filters blood of pathogens

MALT as origin of adaptive response

MALT= mucosal associated lymphoid tissue

• tissues that eliminates pathogens at mucosal surfaces before spreading to underlying tissues

• includes: adenoids, tonsils, Payer’s patches of the gut, respiratory tract, GU tract, appendix

lymph nodes at origin of adaptive response

• Immune surveillance of lymphatic fluid returning from the tissues

• Over 1000 in body

• Become swollen during infection and may be palpated or visually seen

how does lymph fluid enter and leave lymph node

• enter via afferent lymph vessels

• leave by efferent vessels

why are lymph vessels important

allows for slow flow to make sure resident T and B cells have enough time to interact with pathogens

what kind of cells do lymph nodes contain

• macrophages and dendritic cells that have migrated from infected tissue

• this is where adaptive and innate immune systems interact

lymph nodes during infection

• contain actively proliferating B cells which are largely found within germinal centers of the cortex

• B cells will differentiate into antibody secreting plasma cells and migrate to the medulla or enter body tissues where they carry out their immune functions

structure of a lymph node

T vs B cell origin

T cell

• red bone marrow

B cell

• red bone marrow

T vs B cell site of maturation

T cell

• thymus

B cell

• red bone marrow

T vs B cell nature of response

T cell

• cell-mediated

• secreted cytokines

B cell

• humoral (antibodies)

T vs B cell target pathogen

T cell

• intracellular pathogens and cancers

B cells

• extracellular pathogens

look between T (first pic) and B cell (second pic)

what is the importance of t and b cell receptors

• create specificity

• both receptors only specific for one antigen or pathogenic determinant because all receptors will be identical

T cell receptors

• only recognize antigens that have first been processed by specialized immune cells known as antigen presenting cells (APCs)

• APCs process protein antigens by breaking them down into 12-18 amino acid segments that are then packaged and presented to T cells via cell surface receptors termed MHC (major histocompatibility complex)

B cell receptors

recognized unprocessed (native) antigens so no need for APCs

how many pathogenic determinants are there

10^12 since only each recognize one antigen

T cell receptor structure

2 polypeptide chains:

• one alpha

• one B chain

T cell receptor antigen recognition

bind processed antigen in the context of MHC

B cell receptor structure

• modified antibody

• 4 polypeptide chains:

  • 2 identical heavy chains

  • 2 identical light chains

  • *heave chains make up the inner v/y

B cell receptor antigen recognition

bind native antigen

somatic recombination

random combination of DNA segments in T and B cell receptor gene regions to create permutations (like shuffling a deck of cards)

different concepts in somatic recombination

• VDJ segments

• point mutations, deletions, insertions

VDJ segments

• random selection fo one V, D, and J segment to be joined (B cell)

• V D and J gene segments located on different chromosomes (T cell)

purpose of point mutations, deletions, and insertions

to increase numbe rof possible permutations done before transcription

end result of somatic recombination

array of unique T cell and B cell receptors

how can somatic recombination result in autoimmune disorders

sometimes it can lead to the generation of receptors that recognize self antigens

2 categories for autoimmune disorders

• cell mediated

• anti-body mediated

cell mediated autoimmune disorders

• multiple sclerosis

• type 1 DM

multiple sclerosis description

•  progressive neurodegenerative disorder involving demyelination of CNS axons

MS immunological mechanism

• cytotoxic T cells target myelin basic protein expressed by CNS oligodendrocytes

T1DM description

• endocrine disorder resulting in hyperglycemia due to insulin insufficiency

T1DM immunologic mechanism

cytotoxic T cells selectively destroy pancreatic beta cells (auto-antibodies against islet cells and insulin also produced)

antibody mediated autoimmune diseases

• systemic lupus erythematous

• myasthenia gravis

• grave’s disease

• rheumatoid arthritis

• glomerulonephritis

myasthenia gravis description

•  a neuromuscular disease resulting in progressive weakening or paralysis of skeletal muscle

myasthenia gravis immunologic mechanism

auto-antibodies bind ACh receptors at the neuromuscular junction and induce changes in the postsynaptic membrane, interfering with neuromuscular transmission

grave’s disease description

thyroid disorder resulting in overproduction of thyroid hormone (thyroxine) leading the diffuse goitre and exophthalmos

grave’s disease immunological mechanism

autoantibodies bind to and stimulate thyroid-stimulating hormone receptors (TSH-R) on follicle cells

rheumatoid arthritis description

chronic inflammatory disorder of synovial joint

rheumatoid arthritis immunologic mechanism

auto-antibodies (rheumatoid factor) bind IgG, forming immune complexes in synovial joints resulting in synovitis with destruction of articular cartilage and bone

glomerulonephritis description

impairment of renal function due to inflammation of glomerular basement membrane

glomerulonephritis immunologic mechanism

autoantibodies directed against antigens in basement membrane or trapped antigen-antibody complexes (ex. SLE) induce glomerular inflammation leading to renal dysfunction

systemic lupus erythematous (SLE) description

• chronic, complex, multisystem, inflammatory disease

  • Inflammation from deposition of immune complexes within various organs throughout body which may be affected concurrently or one at a time

SLE immunologic mechanism

• Immune complex mediated (type III hypersensitivity reaction)

  • Composed of IgG antibodies and nuclear antigens such as DNA and histones although IgG antibodies may also complex with erythrocytes, coagulation factors, lymphocytes, and platelets as well

• Auto-antibodies commonly produced against nuclear proteins (nucleic acids, histones, ribonucleoproteins)

  • Nuclear antigens often appear in circulation following cell damage associated with trauma, certain drugs (hydralazine), and infections

clinical manifestations of SLE

• Arthritis (90%)

• Vasculitis and rash (70-80%)

• Renal disease (40-50%)

• Anemia (50%)

• Cardiovascular disease (30-40%)

• Butterfly rash

  • Result of exposure to UVB radiation because of release of nuclear antigens from the skin

are male or female more prone to SLE

• females

• 10:1

• suggests that estrogen may favour development of SLE while androgens may be protective

what is the goal of SLE treatment

to control the severity of symptoms

pharmacological SLE treatment

• NSAIDs

• corticosteroids

• immunosuppressives

• antimalarials

• biogenic

• IL-2 therapy

NSAIDs for SLE

• reduce inflammation adn pain by inhibiting cyclooxygenase enzymes responsible for generating prostaglandins

corticosteroids for SLE

• for acute, active disease by reducing immune activity

• many undesirable side effects

immunosuppressives

• including methotrexate (apo-methotrexate) and azathioprine (imuran) to treat severe symptoms involving internal organs

• Interrupt lymphocyte replication by halting cell division resulting in decreased antibody production and a decline in Lupus-related immune complexes

antimalarials for SLE

•  reduce antigen processing by APCs

• Reduce need for corticosteroids

• Inhibit early events of antigen processing and cytokine production by macrophages, reducing lymphocyte activation and then autoantibody production

biologics for SLE

• BLyS inhibitor (belimumab) reduces B cell survival in active disease

• Belimumab reduces B cell numbers so autoantibody titres that, if left unchecked, would otherwise promote immune-complex formation and exacerbate SLE symptoms

• Trials indicate that belimumab + standard therapy → decrease severity of SLE symptoms and reduce corticosteroid use

  • Approved in Canada for use as adjunct therapy in those with active, autoantibody positive SLE

  • Ex of biologics: vaccines, blood, blood components (antibodies), and recombinant proteins

IL-2 therapy for SLE

• promotes T reg cell (regulatory T helper cells) survival

• These cells are important in preventing inappropriate immune responses by reducing the action of lymphocytes

• This cell population is reduced in SLE

• Still being investigated

T cell development

• Begin with process called positive selection/MHC restriction

• Development only continues if T cell that has receptors that can interact with MHC molecules on thymic cells

• If it cannot bind to MHC it is useless because cannot communicate to other immune cells

  • “Dead weight” that the immune system call ill afford

  • Will receive signal to undergo apoptosis

• Those that continue will undergo negative selection/clonal deletion

  • Specialized thymic epithelial cells present self antigens to developing T cells in the context of MHC

  • Most T cells that bind strongly to self antigens undergo apoptosis in thymus (prevents autoimmune disease)

  • T cells that do not bind to self antigens migrate to secondary lymphoid tissues where contribute to working T cells

• In thymus also undergo positive selection to ensure that immunocompetent lymphocytes are allowed to develop, but also rise to a form of self-tolerance called “central tolerance”

• Sometimes autoreactive T cells escape negative selection

  • These cells become regulatory T cells that function to suppress immune responses directed against self antigens

  • Alternatively, autoreactive T cells may be inactivated (called anergy)

    • Due to activation of T cells requiring additional signals from other immune cells, which are not present unless the immune system is actively employed in fending off an infection

• Together the development of regulatory T cells and induction of anergy help make “peripheral tolerance”

  • Peripheral: adaptive cells are regulated in the secondary or peripheral lymphoid tissues

B cell development

• Similar except recognition of MHC by B cell receptor will result in apoptosis

• Recognition of MHC molecules would indicate that a B cell is autoreactive

  • Problem because all nucleated cells in body express MHC

• While B cells do undergo limited negative selection within the red bone narrow, autoreactive B cells can be induced to change their BCR

• In effect they undergo second round of somatic recombination

• If successful, B cells contribute to working population

• For most part anergy is main mechanism for preventing B cell mediated autoimmune responses if autoreactive B cells make their way out of the bone marrow

measures that prevent autoimmunity

• negative selection (clonal deletion) leads to apoptosis

• need for costimulatory molecules

• anergy

• regulatory T cells

need for costimulatory molecules

• Need for T cells and B cells to become fully activated antigen presenting cells

  • Ex. CD80 surface molecule indicated on antigen presenting cell (APC)

• Antigen presenting cells only express these costimulatory molecules when they receive danger signals released by innate immune cells or damaged tissues during an ongoing infection

• Important to keep both humoral and cellular immunity under tight control

anergy

• If an antigen presenting cell does not express the costimulatory signals, its interaction with a T cell or B cell in the lymph node will invariably induce state of anergy

• Antigen presentation without costimulation will inactivate lymphocytes, making it even more difficult to activate them in the future

• Sometimes anergic lymphocytes will undergo apoptosis and cease to be a burden on the immune system

regulatory T cells

• Produced during thymic education

• Function to inhibit or suppress activities of autoreactive lymphocytes, contributing to peripheral tolerance and ensuring that autoimmune diseases do not arise

reasons autoimmunity may arise

• break-dwon of central and/or peripheral tolerance

• molecular mimicry

• appearance of new self antigens

• genetic predisposition

• gender

molecular mimicry

• Ex. rheumatoid fever: antibodies produced during strep infection target bacterial M-proteins and may cross-react with self antigens expressed in the heart, resulting in long lasting damage to the heart muscle and valves (rheumatic heart disease)

  • Streptococcal antigens resemble or mimic self-antigens

  • The antibodies can cross react with self antigens in the joints and kidneys, leading to arthritis or glomerulonephritis respectively

3 situations where appearance of new self antigens occurs

• When mutations is host genes result in the expression of new proteins on cell surface (cancers)

• When self-antigens become altered by attachment of small molecules (like drugs or toxins) effectively rendering them foreign in the eyes of the adaptive response

  • Small nodules (haptens) are incapable of evoking an immune response on their own

• Tissue trauma may cause release of self-antigens that were previously sequestered from the immune system

  • Ex. release of spermatozoa during vasectomy or testicular trauma, exposure of cornea or lens antigens following eye/contact lens trauma, exposure of cardiac muscle following MI

gender and autoimmunity

women are more susceptible (hormones play a role in regulation)

how are T cells identified

based on surface receptor expressed

what is CD

• cluster of differentiation

• act as co-receptors during immune activation

types of T cells

• cytotoxic

• helper

• regulatory

cytotoxic T cells

• CD 8+

• targeted destruction of infected or abnormal cells

helper T cells

• CD4+

• regulates activities of T-cells and B cells

• secretes cytokines that regulate innate and adaptive immunity

• 2 types

  • Th1: secretes IFN-y

  • Th2- secretes IL-4

• *Th17- secretes IL-17

regulatory T cells

• CD4+ and CD25+

• mainly suppresses adaptive immune responses

• prevents autoimmune disease

• secretes IL-10