IMMUNOLOGY

Agustin AC Agustin AM
Balmaceda Cerezo Caluya
Doloroso
 Outline
Immune System Overview
Evaluation of the Immune System
T Lymphocytes, B Lymphocytes, and Natural
Killer Cells
Primary Defects of Antibody Production
Primary Defects of Cellular Immunity
Primary Combined Antibody and Cellular
Immunodeficiencies
Rebecca H. Buckley

T LYMPHOCYTES, B LYMPHOCYTES,
AND NATURAL KILLER CELLS
 LYMPHOPOIESIS IN THE FETUS

Origin of the Lymphoid System:

Pluripotential Hematopoietic Stem cell

2.5 3wk gestation yolk sac

5 wk gestation fetal liver
8 wk gestation bone marrow

Lymphoid Stem Cells T cells, B cells or

NK cells
Primary Lymphoid Organs:
Thymus
Bone marrow
Secondary Lymphoid Organs:
Spleen
Lymph nodes
Tonsils
Peyer Patches
Lamina Propria
T and B lymphocytes
Only components of Immune system with antigen-specific recognition capabilities
Responsible for adaptive immunity

NK Cells
Host defense against viral infections, tumor surveillance and immune regulation
Do not have antigen receptors

Cytokines
promote & facilitate differentiation & proliferation of the cells of immune system
 T-Cell Development & Differentiation

Primitive Thymic Rudiment

4th week of Gestation: Ectoderm (3rd branchial cleft) & endoderm (3rd branchial
pouch) 7th-8th week of Gestation: Move caudally & fuse at midline

Lymphoid cell precursors

Express CD44, c-kit (CD117) & -chain of IL-2 receptor
Presence of small amounts of pre-T : on cell surface in association with CD3
triggers rapid proliferation, loss of CD25 & termination of -chain gene
rearrangement
Double-positive thymocytes rearrangement of -chain locus, express low
levels of : T-cell receptor & associated CD3 complex thymic selection
 T-Cell Development & Differentiation

Positive selection Negative Selection

interaction of immature Occur in medulla
thymocytes Mediated by surviving
Express low levels of TCR, with thymocytes with higher levels of
MHC antigens present on cortical TCR expression with host peptides
thymic epithelial cells presented by HLA class I or II
Thymocyte with TCR capable of Mediates apoptosis of
interacting with foreign antigens autoreactive thymocytes
are activated & develop to
maturity
>98% die
some mature into CD4 or CD8
single positive cells
 T-Cell Development & Differentiation
11-12 wk of embryonic life appendix
14-15 wk of embryonic life tonsils
16-18 wk of embryonic life (+) Hassalls corpuscles (bodies) in thymic medulla
Heaviest concentration paracortical areas of lymph nodes, periarteriolar areas of
the spleen and thoracic duct lymph
12 wk gestation T cells proliferate in response to plant lectins
Phytohemagglutinin
Concanavalin A
20 wk gestation (+) antigen-binding T cells

L-selectin
direct homing of lymphocytes to peripheral lymphoid organs
 B-Cell Development & Differentiation

B cell development: fetal liver 7th week of gestation

Fetal CD34 seeded to bone marrow of clavicles (8th week) & long bones
(10th week)
B cell differentiation rearrangement of immunoglobulin gene segments
to generate a diverse repertoire of antigen receptors

7-11 wk of gestation sIgM+ & sIgG+ B cells

12-13 wk of gestation sIgD+ & sIgA+ B cells
 Stages of Development
Early pro-B cell Pre-B cell
Ig light chaains are
1st descendent of Late pro-B cell rearranged
pluripotential stem V segment Expression of
cell committed to B- rearranges to a D-J cytoplasmic heavy
lineage gene segment chains but no sIgM
development Cells with Must rearrange the
Heavy chain locus productive same light gene on
rearranges first rearrangements will both chromosomes
D-J rearrangement survive for a productive
on both
rearrangement
chromosomes
Present in fetal liver
at 7 wk gestation

Mature or Virgin Immature B-cell

Light chain genes
B cell have been
Co-expresses both rearranged and
sIgM & sIgD sIgM is expressed
 Antigen-Dependent Stages:
Develop after the mature B cell is stimulated by antigen differentiation into sIg+
memory (CD27) B cells & plasma cells
Plasma cells secrete antigen-specific antibody
Deficiency of activation-induced cytidine deaminase (AICDA) or uracil DNA glycosylase
(UNG) autosomal recessive hyper IgM failure of isotype switching
Only IgM antibodies are formed

Immunoglobulin Isotypes:
IgG & IgM only complement-fixing isotypes
Immunoglobulin Isotypes: Most important Ig for protection against infectious
IgM agents
IgG IgM confined in intravascular compartment
IgA IgG present in all internal body fluids
IgD Transplacental transfer
IgE IgG2 least ability to cross the placenta
IgA major protective Ig of external secretions
IgE host defense against parasites
Principal mediator of immediate allergic reactions
 Natural Killer-Cell Development

Present in human fetal liver cells at 8-11 wk of gestation

Derived from bone marrow precursors
Represent 8-10%
functional capacity to mediate non-antigen specific cytotoxicity
Express CD56 & CD16 (FcRIII)
Humans with autosomal recessive SCID with profound deficiencies in T & B cells
abundant NK cells
X-linked & Jak3-deficient SCID (-) T or NK cells
 Immune Cell Interactions

T-cell Receptor
Recognize only processed antigenic peptides
Class I MHC
Present in all nucleated cells
Class II MHC
present in antigen-presentng cells (APC)
Macrophage
Dendritic cells
B cells
Main Functions of T cells:
Signal B cells to make antibody
Kill virally infected cells or tumor cells
Th cells
stimulated to make interleukins & upregulate cell surface molecules
CD40 ligand provide help for B cells
Cytotoxic T cells Stimulated to kill their targets
Primary Antibody Response
B cells develops into an antibody-producing plasma cell
Cross-linking of CD40 on B cells by CD154 on T cells in the presence of cytokines
causes the B cells to undergo proliferation & to initiate Ig synthesis
Only IgM antibody is made

Secondary Antibody Response

More rapid generation of cells
IgG, IgA, or IgE antibodies are made

NK-Mediated Lysis
Binding to target is of crucial importance

Antibody-dependent cellular cytotoxicity

Antibody is bound through its Fc region to the FcRIII
 POSTNATAL LYMPHOPOIESIS
T Cells & T-Cell Subsets
T cells present in higher numbers due to higher absolute lymphocyte count in infants
Higher CD4 to CD8 T cells in cord blood
Represent 8-10% of lymphocytes
Slightly lower percentage present in blood cord
Th1 cells
Produce IL-2 & IFN-
Promote cytotoxic T-cell or delayed hypersensitivity types of responses
Th2 cells
Produce IL-4, IL-5, IL-, IL-13, IL-21
Promote B cell responses & allergic sensitization
Th17 cells
Produce IL-17, IL-21
IL-21 activate STAT3 required for further development of Th17 effector
activity
Promotes inflammation
Treg cells
CD25 high + T cells
Important in the prevention of autoimmune diseases & T cells that have
phenotypic characteristics of NK cells (NKT cells)
B Cells & Immunoglobulins
IgM antibodies render infants more susceptible to Gram-negative bacterial
infections
C3b low concentration in newborn serum
IgG antibodies fight against Gram-positive bacteria
Relative deficiency of IgG2 deficient antibodies against capsular
polysaccharide antigens
Premature infants low serum opsonic activity against all types of organisms
B lymphocytes
present in cord blood in slightly higher percentages & considerably in higher
numbers in blood of children and adults
Higher absolute lymphocyte count in all normal infants
Serum IgA detected at 13th day of post-natal life reaching adult levels by 6-7y/o
Maternal IgG disappear during 6-8 month of life
Increased rate of IgG synthesis reaching adult concentration by 7-8y/o

Natural Killer cells

Percentage in cord blood is usually lower than in the blood of children & adults
Same absolute number due to higher lymphocyte count
Capacity of cord blood NK cells is 2/3 that of adults
 Lymphoid Organ Development
Small but well developed at birth & matures rapidly during the postnatal period

Thymus
Largest during the fetal life & at birth
Peak mass: puberty
1 year of age
All lymphoid structures are mature
Peak peripheral lymphocyte counts
6 year of age
Peripheral lymphoid tissue reaches adult size
Undergo involution with puberty
Spleen
Reach full weight until adulthoood
Peyer Patches
At birth: 50% of the adult number
Adolescent: exceeds adult number
 INHERITANCE OF ABNORMALITIES IN T-, B- AND NK-CELL
DEVELOPMENT
Recessive traits
Caused by X chromosome mutations and autosomal mutations

Molecular Basis of Autosomal Defects

Abnormalities of purine salvage pathway enzymes
Adenosine deaminase (chromosome 20q13-ter)
Purine nucleoside phosphorylase (chromosome 14q13.1)
Mutations in gene encoding ZAP-70
Chromosome 2q12
Important in T-cell signaling
Mutation on chromosome 19p13.1
Encodes Jak3
Primary signal transducer from cytokine receptor chain
Mutation on genes on chromosome 11
Encode components of TCR
CD3 ,, and
Mutation in recombinase activating genes (RAG1 & RAG2)
Mutation in gene on chromosome 5p13
Encodes of il-17 receptor
 PRENATAL DIAGNOSIS AND CARRIER DETECTION
Amnion cell enzyme analyses
Permit intrauterine diagnosis of deaminase and purine nucleoside
phosphorylase deficiencies
Fresh or cultured amnion cell
Sample obtained before 20 wk gestation
Direct mutation analysis
Chorionic biopsy or Amniocentesis
Permit diagnosis of:
X-lnked or Autosomal defects causing SCID
Severe T-cell deficiency
cMHC class I and/or II antigen deficiencies
Chronic granulomatous diseases
Wiskott-Aldrich syndrome
Fetoscopy
18-22 wk of gestation
Carried out if mutation is not known to occur in the family