Specific (adaptive) Specific (adaptive) immunity immunity Immunology, 3rd year
Jan 13, 2016
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