Specific (adaptive) immunity Immunology, 3rd year.

Specific (adaptive) immunitySpecific (adaptive) immunity

Immunology, 3rd year

ContentsContentsSpecific immunity: Basics Immunoglobulins and T cell receptorB and T developmentT cell function Innate-like lymphocytesExamples: B and T cell function

Characters and castCharacters and cast

T+

Non-specific, innate Specific, adaptive

Components of immunityComponents of immunity

innate adaptive

cellular neutrophils T lymphocytes monocytes-

macrophages, DC, NK cells

humoral complement antibodies acute phase (B lymphocytes) proteins (CRP,MBL..)

Differences between innate and Differences between innate and adaptive immunityadaptive immunity

innateinnate adaptiveadaptive

phylogeneticphylogenetic olderolder youngeryounger

reaction/speedreaction/speed minutesminutes hours-dayshours-days

immun. memoryimmun. memory nono yesyes

Ag receptorAg receptor shared structuresshared structuresindirect –opsonines; indirect –opsonines; all cells identically all cells identically equippedequipped

Ig, TCR,Ig, TCR,diverse diverse repertoire, clonesrepertoire, clones

??• types of antibodies: why and when they types of antibodies: why and when they

are importantare important• molecular basis of immune memorymolecular basis of immune memory• what can I learn from serology in infantswhat can I learn from serology in infants• how do I find out which lymphocytes are how do I find out which lymphocytes are

(mono)clonal(mono)clonal• what are CD3 etc.? which other CDs do I what are CD3 etc.? which other CDs do I

need to memorizeneed to memorize• how do the antibodies improve in the how do the antibodies improve in the

nodesnodes• weapons of the immune killersweapons of the immune killers• what happens to T and B lymphocytes what happens to T and B lymphocytes

during EBV infectionduring EBV infection• why is why is Haemophilus influenzaeHaemophilus influenzae dangerous dangerous

to native American kids?to native American kids?• ……

ContentsContentsSpecific immunity: Basics Immunoglobulins and T cell receptorB and T developmentT cell function Innate-like lymphocytesExamples: B and T cell function

Antibody (immunoglobulin) Antibody (immunoglobulin) structurestructure

,,,,,,,,

variable part(Ag binding)

constant part(function)

Antibody functionsAntibody functions•neutralizing

•opsonization

•complement activation

•sensitizing for NK cell killing (ADCC), or for granulocyte activation

•mast cell sensitizing

IgG, IgAIgG, IgA

IgGIgG

IgM, IgG3 >G1>G2,IgAIgM, IgG3 >G1>G2,IgA

IgGIgG

IgEIgE

IsotypesIsotypes

Ig isotypes, factsIg isotypes, facts

Iso type

Mol mass

Serum conc Localization T (1/2)biol Function

(kDa) (g/l) (days)

IgG 155 8-18serum, intersticialfluid 21

opsonization; neutralization; crosses placenta; secondaryí response

IgA 160-350

0.9-3.5serum, mucosae, tears, saliva

6mucosal defense, opsonization

IgM 900 0.9-2.5serum, B-cell surface

6complement activation; primaryresponse; Ag receptor

IgD 180 0.1 3Ag receptor

IgE 190 3x10-4 2anti-parasite defense

serum, B-cell surface

serum, intersticialfluid

Ig after birth, physiological Ig after birth, physiological infantsinfants

% of adult values

maternal IgG (trans-placental)

gestation age (wks)

birthage (yrs)

FcRn: neonatal FcRFcRn: neonatal FcR

transport across placentaextends T1/2

Beta-2-microglobulin

FcRn

Antibody responseAntibody response

Primary antigenic sinPrimary antigenic sin

ABCD A C EF A D E G

B cell receptorB cell receptor

T Cell ReceptorT Cell Receptor

NK cells: no specific NK cells: no specific antigen receptorantigen receptor

CD nomenclatureCD nomenclatureCD3 = T lineageCD4 = T helpers*CD8 = cytotoxic T*CD19 = B lineageCD10 = immature lymphoid cells*CD34 = progenitors*

*also other cells CD40/CD40L

Adaptive immunity:Adaptive immunity:

B lymphoB lymphoT lymphoT lympho

Ag react with:Ag react with:

IgIgTCRTCR

IgM: first isotype after primary infectionIgM: first isotype after primary infection

MMDD GG AA

EE

[structure, function][structure, function]

IgG: IgG: main isotype of long-lasting defense, main isotype of long-lasting defense, crosses placentacrosses placenta

ContentsContentsSpecific immunity: Basics Immunoglobulins and T cell receptorB and T developmentT cell function Innate-like lymphocytesExamples: B and T cell function

Antigen specifity - clonal theoryAntigen specifity - clonal theory

Immunoreceptor gene Immunoreceptor gene rearrangementrearrangement

V D J

Genes for various chains..Genes for various chains..

Allelic exclusion

B lymphocytes - developmentB lymphocytes - development

Germinal center close-upGerminal center close-up

nemůžu najít obrázek

Somatic hypermutationSomatic hypermutationmutation in variable loci Ig genesin germinal centerstogether with isotype switch

AID (aktivation induced deaminase)

Thymus-independent (TI) antigensThymus-independent (TI) antigens

Type 2:Type 2: - repetitive structures (often - repetitive structures (often polysaccharides)polysaccharides)

- no help: IgM only- no help: IgM only- mostly created by B1 cells or by marginal - mostly created by B1 cells or by marginal

zoneszones- children under 2 yrs: weak response- children under 2 yrs: weak response

Type 1:Type 1: mitogenic potential (e.g. mitogenic potential (e.g.: lipopolysacharide: lipopolysacharide))

T cell developmentT cell development

T lymphocyte subpopulationsT lymphocyte subpopulations

CD 8 - Tc, cytotoxic lymphocytes

CD4 - Th - helpers, Treg- regulatory [attacked by HIV]

Normal frequency in blood: CD4/CD8 cca 2

ContentsContentsSpecific immunity: Basics Immunoglobulins and T cell receptorB and T developmentT cell function Innate-like lymphocytesExamples: B and T cell function

Cytotoxic T lymphocyteCytotoxic T lymphocyte

NK a Tc cells: granulesNK a Tc cells: granules

perforin granzymesgranulysin

Cytotoxic T lymphocyte: other Cytotoxic T lymphocyte: other mechanismsmechanisms

Fas ligand

cytokines interferon γTNF αTNF β

Th cells as effectorTh cells as effector

If macrophages cannot eat it..If macrophages cannot eat it..

Regulatory role of CD4+ cellsRegulatory role of CD4+ cells

Th0

Th3Th1 Th2

Treg

IFN-LFIL-2

IL-4, -5, -6IL-10TGF-IL-13

IFN- IL-12

IL-4

cellular immunity humoral immunity

Th-helpersTh-helpers Regulatory TRegulatory T

Allergy:Allergy:possible role of possible role of

T[reg] cellsT[reg] cells

ContentsContentsSpecific immunity: Basics Immunoglobulins and T cell receptorB and T developmentT cell function Innate-like lymphocytesExamples: B and T cell function

Innate-like lymphocytesInnate-like lymphocytes

limited repertoirspecific function and localizationmostly autonomous

TγδB1NKT

•Diversity stems from Diversity stems from rearrangements of genesrearrangements of genes•All lymphocytes arise from All lymphocytes arise from bone marrow precursorsbone marrow precursors•Autoreactive lymphocytes dieAutoreactive lymphocytes die•Non-productive and areactive Non-productive and areactive lymphocytes dielymphocytes die

•Somatic hypermutation of B lymphocytes leads to the Somatic hypermutation of B lymphocytes leads to the selection of the best Igselection of the best Ig•Main T lymphocyte subsets are Th (CD4+) and Tc (CD8+)Main T lymphocyte subsets are Th (CD4+) and Tc (CD8+)•Th comprise of Th1 and Th2, related are Th3 and Tr1 with Th comprise of Th1 and Th2, related are Th3 and Tr1 with regulatory functionregulatory function

ContentsContentsSpecific immunity: Basics Immunoglobulins and T cell receptorB and T developmentT cell function Innate-like lymphocytesExamples: B and T cell function

B and T lymphocyte disordersB and T lymphocyte disorders

decreased productioninborn errors (T, B, T and B)malnutritionTB and other infections

increased destruction steroids, radiation, chemotherapy

AIDS (T)

losses (gut, chylothorax,..) (T and B)

- lymphopenia:

B and T lymphocyte disordersB and T lymphocyte disorders

normal absolute counts vary throughout agevirus infectionsother infections (mycoplasma, syphilis, ..)dif. dg.: clonal proliferations (incl. leukemias)

- lymphocytosis:

B and T lymphocyte disordersB and T lymphocyte disorders

antibody deficiencyIgA

hereditary mutation CD40/CD40L

polymorphism of V(D)J in some ethnic groups

- functional defects:

EBV, Epstein-Barr virusEBV, Epstein-Barr virus

•infants, preschool kids: mostly asymptomatic or infants, preschool kids: mostly asymptomatic or indistinguishable from other infectionsindistinguishable from other infections•adolescence (rarely at different age): inf. mononucleosis adolescence (rarely at different age): inf. mononucleosis

•Primoinfection:Primoinfection:

•95% world population95% world population

Life cycle, EBVLife cycle, EBV

+fever

Infectious mononucleosis: clinicsInfectious mononucleosis: clinics

splenomegaly up to 50% patientshepatomegaly (10%)elevated transaminases, LDHpetechiae na patřeeye-lid oedemasexanthemas (up to 15%)(typically no stomachache)

Severe EBV complicationsSevere EBV complications

virus-associated hemophagocytic syndrome

X-linked lymphoproliferationfamiliar hemofagocytic lymfohistiocytosis

malignities: nasofaryngeal carcinomaendemic Burkitt lymphomaother malignancies (Hodgkin, ...)

Severe lymphoproliferations

Burkitt lymphomaBurkitt lymphoma

perforin deficiencyperforin deficiency

T+

Imunodeficiencies: not just lossesImunodeficiencies: not just lossesAutoimmune lymphoproliferative syndromeAutoimmune lymphoproliferative syndrome

hyper-Ighyper-Igsplenomegalysplenomegalylymphadenopathylymphadenopathyautoimmunityautoimmunityincreased CD3+TCRαβ+CD4-CD8- cellsincreased CD3+TCRαβ+CD4-CD8- cellsrisk of lymphomasrisk of lymphomas

Genetic causes of ALPSGenetic causes of ALPS

ALPS3: the clue ALPS3: the clue