El sistema inmune: un mundo por descubrir

Inmunología Básica
Mayo, 2011

Persio D. López

Thursday, May 12, 2011

 El sistema inmune: un mundo por descubrir
Inmunología Básica
Mayo, 2011

Persio D. López

Thursday, May 12, 2011

 ¿Qué veremos hoy?

Detallitos que no podemos olvidar

Los líderes del mundo de Aslan

Los obreros del mundo de Aslan

Thursday, May 12, 2011

 Los detalles que no podemos olvidar

Thursday, May 12, 2011

 Megakaryocyte–
erythrocyte Erythrocytes
progenitor

Common
myeloid
precursor
Megakaryocytes

Stem cell

Lin– Granulocyte–
monocyte Granulocytes
Sca1+
cKit+ ? progenitor
Thy1low
CD34low/+ Lin–
Sca1–
cKit+ Resident Macrophages
Thy1– monocytes and DCs
CD34+
CD16+
Common lymphoid CD32+
precursor

Inflammatory
monocytes

DC precursors DCs

T cells NK cells B cells Blood Tissue

Figure 1 | Origin and haematopoietic differentiation of myeloid antigen-presenting cells. The stem cells in bone
Imhof B, Aurrand-Lions M. Adhesion mechanisms regulating
marrow differentiate into myeloid or lymphoid precursor cells. The granulocyte–monocyte progenitors derive from the

La familia y la casa
the migration of monocytes. Nat Rev Immunol.
common myeloid precursor cell. At this stage, they express CD16 and CD32 on2004;4:432-444.
the cell surface andFigure
enter the
1, terminal-
Origin and haematopoietic
differentiation stage, which leads to differentiation into granulocytes and monocytes that subsequently exit from the bone
differentiation of myeloid antigen-presenting cells; p. 433.
marrow into the blood. After recruitment to peripheral tissues, monocytes can then further differentiate into dendritic cells
(DCs) or macrophages. This plasticity in differentiation pathways contrasts with circulating DC precursors, which can only
differentiate into myeloid or lymphoid DCs. NK, natural killer.
Thursday, May 12, 2011
 Ontogenesis Primary lymphoid organs Secondary
lymphoid organs
Progenitor cell
Medulla
Epithelium
IL-1
IL-2
Dendritic IL-6 Spleen
cells IL-7

Cortex Macro-
phages T lymphocytes

Fetal liver

'()*+,#)-+. /$%)0%1.#2
Thymus T lymphocytes

Myelopoietic
progenitor cell
Pluripotent
stem cell
?

"
Bone marrow B lymphocytes Lymph nodes
Lymphatic
progenitor cell
Progenitor cell

Sinus
IL-1
IL-6
IL-7
Erythron Stroma

Mucosa-associated
B lymphocyte
lymphoid tissue
A. Structure of the lymphoid system
Burmester G-R, Pezzutto A, Ulrichs T, Aicher A. Color atlas

La familia y la casa Liver

of immunology. Stuttgart ; New York: Thieme; 2003. Figure
2a, Structure of the lymphoid system; p. 5.

Thursday, May 12, 2011 Lung Spleen

 Abbas AK, Lichtman AH. Cellular and molecular

Defensa innata immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

Figure 1.1; p. 4.

Thursday, May 12, 2011

 Peptidoglycan (Gram-positive) protein A1 (BCL2A1), in
Lipoteichoic acids (Gram-negative) sis 1 (cIAP1), cIAP2, XIA
Lipoproteins LPS (Gram-negative) members51. However, in
Lipoarabinomannan Endogenous ligands
(Mycobacteria) intracellular bacteria and
Zymosan (yeast) Flagellin induce cell-autonomous
CD14 TLR4 TICAM1, FADD, caspas
TLR5
TLR6 MD2 Profilin-like kinase R (PKR)52–55 or th
CD36 (Toxoplasma gondii)
Uropathogen? of type I interferons. In a
TLR2 natural killer (NK) cells
TLR1 infected cells either by d
TLR11
TLRs on NK cells or the
such as type I interferon
TIRAP TRIF
MYD88 TRAM
TLRs, tissue repair and
TLR7 In addition to their role
defence from microbial
are involved in various a
ssRNA homeostasis, including t
regeneration57,58. Tissue r
NF-
B, IRF and restoration of lost cell po
MAPK signaling Unmethylated TLR3 architecture, blood supp
CpG DNA
tion, and TLRs appear to
dsRNA
though multiple mechan
ing pro-survival signals
apoptosis, TLRs may dic
TLR9 of injury and cell death,
extent of initial tissue inj
signalling induced after
Figure 1 | Physiological functions of Toll-like receptors (TLRs). TLRs are involved in recognition TLR-dependent product
of microbial and endogenously derived molecular patterns. This occurs both at the plasma membrane
Nature Reviews | Cancer dins (through cyclooxyg
Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and

Defensa innata
and at intracellular compartments. After ligation of TLR ligands either
accessory molecules such as CD14, MD2 (also known as LY96) and CD36,
directly
cancer. Nat or
Physiological
withCancer.
Rev
functions
TLRs dimerize
the help 2009;9:57-63.
andof transmit
of induction)Figure
in tissue1,strom
Toll-like receptors (TLRs); p. 58.
ulation of anti-apoptotic
signals throughout the cell by means of adaptor molecules such as myeloid differentiation factor 88
(MYD88) and TRIF. This leads to the activation of multiple cellular phenomena, the best-described of signals to keep both dif
which being the activation signal transduction to the nucleus (such as through activation of nuclear progenitor cells within t
Thursday, May 12, 2011 factor-KB (NF-KB), MAPKs and interferon regulatory factors (IRFs). TLR activation leads to regulation In the nervous system
 van Kooyk Y, Geijtenbeek TB. DC-SIGN: escape mechanism

Defensa innata for pathogens. Nat Rev Immunol. 2003;3:697-709. Figure 1,

C-type lectins and Toll-like receptors: pathogen receptors on
dendritic cells; p. 698.

Thursday, May 12, 2011

 Respuestas primarias y Abbas AK, Lichtman AH. Cellular and molecular
immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

secundarias
Figure 1.6; p. 13.

Thursday, May 12, 2011

 Primaria Secundaria

Respuestas primarias y Abbas AK, Lichtman AH. Cellular and molecular

immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

secundarias
Figure 1.6; p. 13.

Thursday, May 12, 2011

 Las respuestas son Abbas AK, Lichtman AH. Cellular and molecular
immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

específicas
Figure 1.7; p. 14.

Thursday, May 12, 2011


CD4+CD25+ REGULATORY
T CELL
Number of thymocytes
(TReg cell). A CD4+ T cell that
expresses high levels of CD25
(also known as the α-chain of
the interleukin-2 receptor), is
naturally anergic and requires
stimulation through the T-cell
receptor for induction of its
cell-mediated suppressive
function. The role of this
subset of T cells is to maintain
self-tolerance.
CD8αα+ INTESTINAL
EPITHELIAL LYMPHOCYTE
A type of T cell that is found in
the intestinal epithelium. The
CD8 molecule that they express
is a homodimer of CD8α,
rather than the CD8αβ
heterodimer that is expressed
by conventional CD8+ T cells in
the lymph nodes. It has been
proposed that these cells are
self-reactive T cells that have
regulatory properties.
NATURAL KILLER T CELL
(NKT cell). A T cell that
expresses both natural killer
Tolerancia a lo propio
(NK)-cell receptors and an
αβ-T-cell receptor (αβ-TCR).
In mice, these cells were first
identified by their expression
of the alloantigen NK1.1 (also
known as NKR-P1C). Some
Thursday, May 12, 2011
Thymus
Martin and Bevan 12
showed that
Death by
neglect small numbers of mature TCR-tr
non-transgenic recipients follow
cognate antigen led to the death o
Positive cytes that were not specific for th
selection
Negative selection: and other reasons, many investi
clonal deletion the use of TCR-transgenic mice
receptor editing cognate antigen of the TCR as
anergy
antigen for the modelling of n
thymocytes by clonal deletion.
A classic model of this type i
which CD8+ T cells that express
is specific for the male antigen
Affinity selected in female mice but del
TCR-transgenic mice tend to fal
Agonist
of clonal deletion: those that del
selection:
TReg cells in development (that is, at the d
CD8αα+ IELs to double positive (DP) stage); a
NKT cells thymocytes late (that is, at the D
(SP) stage). Sometimes these are
Lymph node and medullary deletion, respectiv
DP progenitors reside in the corte
area of the thymus) and SP prog
Provide immune Regulate
responses to immune medulla (which is the inner area)
foreign antigens responses TCR-transgenic mice that have b
Figure 1 | Central-tolerance mechanisms. The affinity of
32 have been used to model clon
the T-cell receptor (TCR) for self-peptide–MHC Hogquist the Baldwin half
ligands isKA, of these,SC.thymocytes
TA, Jameson are dele
Central tolerance:
crucial parameter that drives developmental outcomelearninginself-control
the inment, and in about
the thymus. Nat Revhalf, thymocy
Immunol.
2005;5:772-782. Figure 1, Central tolerance mechanisms; p.
thymus. Progenitors that have no affinity or very773.low affinity die development. (For a complete li
by neglect. This is thought to be the fate of most thymocytes. strains, see Models of negative se
If the TCR has a low affinity for self-peptide–MHC, then the
links box.) One determinant of
progenitor survives and differentiates, a process that is known
versus late clonal deletion is whet
as positive selection. If the progenitor has a high affinity for self-
 a
cTEC

Peptide –MHC Peptide –MHC

complex (low complex (high
affinity for TCR) affinity for TCR)
CD4 Apoptosis-
or CD8 promoting
TCR
factor

Differentiation-
promoting
factor
T cell

Differentiation Apoptosis

b mTEC or DC
Hogquist KA, Baldwin TA, Jameson SC. Central tolerance:
learning self-control in the thymus. Nat Rev Immunol.

Tolerancia a lo propio 2005;5:772-782. Figure 3, Models of how differences in

affinity affect whether differentiation or apoptosis occurs
during development; p. 776.

Thursday, May 12, 2011

 La ley de Murphy van Kooyk Y, Geijtenbeek TB. DC-SIGN: escape mechanism
for pathogens. Nat Rev Immunol. 2003;3:697-709. Figure 2,
HIV-1 subverts intracellular processing by dendritic cells

también aplica through DC-SIGN; p. 703.

Thursday, May 12, 2011

 Entonces, los principios básicos de la inmunidad
son:

• Eliminación de muchos microbios por medio de inmunidad innata no

específica.

• Agentes de la inmunidad innata informan las células de inmunidad adquirida

si es apropiado montar una respuesta (y cuál debe ser orquestada).

• El sistema inmune adquirido es exquisitamente específico.

• El sistema inmune presenta memoria de lo que ha conocido.

• Lo propio debe ser tolerado.

Thursday, May 12, 2011

 Los líderes en el mundo de Aslan

Thursday, May 12, 2011

 Homeland Security: Abbas AK, Lichtman AH. Cellular and molecular
immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

Linfocitos B
Figure 9.1; p. 188.

Thursday, May 12, 2011

 Homeland Security: Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Color
plate 7.1, Differentiation diagram for development of B cells

Linfocitos B from hematopoietic stem cells; p. 238.

Thursday, May 12, 2011

 Homeland Security: Abbas AK, Lichtman AH. Cellular and molecular
immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

Linfocitos B
Figure 3.1, Structure of an antibody molecule; p. 48.

Thursday, May 12, 2011

 Homeland Security: Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Color
Plate 4.2, Ribbon diagram of a complete IgG1 crystal; p.

Linfocitos B 128.

Thursday, May 12, 2011

 V IgG IgA IgM IgD IgE
Serum: Serum: lgM Serum: lgD

.#$/+"-$0+' 12)$3)4'-,
VL Monomeric lgA
CL
SS
SS

SS

IgG1 65%
SS SS

SS

SS

SS
SS
SS

SS
SS
SS
SS

IgG2 23%

"
Secretory Membrane- Membrane-
lgA; dimer bound lgM bound lgD
SS
SS
SS
SS
Hinge
SS SS
SS SS SS
SS
region SS
SS
SS
SS

J
IgG3 8%
S
S chain SS

SS
SS
SS

Mature Mature Basophil

B lymphocyte B lymphocyte granulocyte
IgG4 4%

Serum lg 80% 13% 6% 0.1% 0.002%

Half-life
Homeland
23 6
Security:5
Burmester G-R, Pezzutto A, Ulrichs T, Aicher A. Color atlas
3
of immunology. Stuttgart 2.5 days
; New York: Thieme; 2003. Figure

Linfocitos B
14c, Immunoglobulin structure and features; p. 29.
C. Immunglobulin structure and features

Lumen Fc#R Binding at pH <7.0 Secretory component Lumen

Thursday, May 12, 2011
 n = ~50 Chromosome 14
!

✂
VH1 VH2 VH3 Vn

5' 3'
L1 L2 L3 Ln D1 D2 D 3 D 4 Dn J1 J2 J3 J4 J5 J6 Cµ C% C#3 C#1 C&1 C#2 C#4 C' C&2

DJ rearrangement Deletion Germline DNA

VH1 VH2 VH3 Vn C#4

5' 3'
L1 L2 L3 Ln D1 D2 D3 J5 J6 Cµ C% C#3 C#1 C&1 C#2 C' C&2

Deletion Transcription

1#$2."+$0.' 3-)$4)5'+6
VDJ-rearrangement DJ-Cµ mRNA DJ-Cµ protein
VH1 VH2
Cleavage
5' 3' of L-coded
L1 L 2 D3 J 5 J6 Cµ C% C#3 C#1 C&1 C#2 C#4 C( C&2 sequence

VDJ-Cµ coding mRNA µ heavy

A. Organization and rearrangement of immunoglobulin H genes chains

"
n = ~35
V$1 V$2 V$3 V$n
5'
L1
Homeland Security:
L2 L3 Ln J$1 J$2 J$3 J$4 J$5
Burmester G-R, Pezzutto
3' A, Ulrichs T, Aicher
Chromosome 2 A. Color atlas
of immunology. Stuttgart ; New York: Thieme; 2003. Figure
15a, COrganization and rearrangement of immunoglobulin H

Linfocitos B
$
genes; p. 31.
B. Organization of ! light chain genes

Thursday, May 12, 2011

 Homeland Security: Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure

Linfocitos B
1.4, Two forms of B cell activation; p. 7.

Thursday, May 12, 2011

 Los generales:
Linfocitos T
Thursday, May 12, 2011
 Los generales: Paul WE. Fundamental Immunology. 6th ed. Philadelphia:
Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure
10.3, A model of the αβ T cell receptor (TCR)–CD3 complex;

Linfocitos T p. 318.

Thursday, May 12, 2011

 CD28 ligatio
into IL-4-p
APC APC APC
although th
occurs is not
CD80/86 MHC CD80/86 Whether
TCR CTLA-4 quantitative
CD28 pathways fro
controversy.
T cell T cell T cell some compo
independen
triggered by
the TCR. At
shown to re
Apoptosis Proliferation Cell-cycle arrest
Anergy Differentiation engaged for
Effector function tion to occu
Figure 1 | T-cell fate under different conditions of TCR
T-cell activa
engagement. Simultaneous recognition of a specific major recruits LIPID
Los generales:
histocompatibility complex (MHC)–peptide CD28complex
and CTLA-4. byNat the TDec;1(3):220-8.
Rev Immunol. 2001 cells and
Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by

Figure 1, T-cell fate under different conditions of TCR

T-cell receptor (TCR) and of B7-1 (CD80) or B7-2 (CD86) by
Linfocitos T engagement; p. 221.
the co-stimulatory receptor CD28 results in T-cell activation,
thereby pro
local concen
cytokine production, proliferation and differentiation. In the cules16. At th
Thursday, May 12, 2011
 for the reduced CD4 SP
Capsule could be a reduced co
ligand repertoire. Ho
Thymocyte diverse peptide–MHC
H-2DM-deficient mic
DN3
express only a single pe
port the generation of s
SP T cell compartmen
DN2 DP of Ctsl –/– mice), a mu
Cortex tion also has to be tak
cathepsin L, cTECs ma
DN1 peptides through the
Blood vessel
cTEC thereby rendering th
class II-bound peptide
of tolerogenic APCs in
DCs constitutively use
a disproportionately lar
DC SP be subject to clonal de
mTECs or DCs of the
their positive selection
mTEC
Trabecule
Medulla In order to test this
experimentally elimina
on the CD4 SP T cell r
in bone marrow chima
cells, but not stromal c
so that the positively se
Figure 2 | Stromal cell interactions along the migratory route of developing not censored by clonal
T cells. T cell progenitors enter the thymus through blood vessels near the cortico- that results from encou
Los generales:
thymocytes is accompanied by an outward movement of cells
Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen
medullary junction. Development of sequential stages of double-negative
presentation in the(DN)
towards
tolerance
Indeed,
thymus for positive
the | Immunology
induction.
in and
selection chimaeras
Nat Rev Immunol. 2009 Dec;9(12):
central in
Nature Reviews bone marrow cells are
Linfocitos T 833-44. Figure
sub-capsular zone. After T cell receptor β-selection, double-positive (DP) cells 2, Stromal cell interactions along the
migratory route of developing T cells;size of the CD4 SP T cel
p. 835.
randomly move through the cortex and presumably scan cortical thymic epithelial
cells (cTECs) for positively selecting ligands119–121. After positive selection and CD4 or
increased and was simil
CD8 lineage commitment, single-positive (SP) thymocytes rapidly relocate to the had received MHC class
Thursday, May 12, 2011 This supports the notion
 Los generales: Abbas AK, Lichtman AH. Cellular and molecular
immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

Linfocitos T Figure 8.2; p. 165.

Thursday, May 12, 2011

 Los obreros en el mundo de Aslan

Thursday, May 12, 2011

 CD34+ Pluripotent stem cell

Myeloid Lymphoid
progenitor progenitor

T-cell B-cell
Mega- pre- Thymus pre-
karyocyte Myeloblast Monoblast cursor cursor

Erythroblast

'()*+,#)-+. /$%)0%1.#2
Platelets
B
P lympho-
h cytes
Erythrocytes a
g o e s
c y t
T lympho-
cytes

"
Basophils

Eosinophils Dendritic Natural

Neutrophils Monocytes cells killer cells
A. Origin of cells of the immune system

Innate immunity Adaptive immunity

Infectious Burmester G-R, Pezzutto A, Ulrichs T, Aicher A. Color atlas

Phagocytes Fagocitosagents of immunology. Stuttgart ; New York: Thieme; 2003. Figure

1a, Structure of the lymphoid system; p. 3.

Generation of
Thursday, May 12, 2011 Natural killer cells specific receptors
 Abbas AK, Lichtman AH. Cellular and molecular

Fagocitos immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

Figure 12.3, Receptors and responses of phagocytes; p.
282.

Thursday, May 12, 2011

 Paul WE. Fundamental Immunology. 6th ed. Philadelphia:

El complemento Wolters Kluwer/Lippincott Williams & Wilkins; 2008. Figure

1.12, The complement system; p. 23.

Thursday, May 12, 2011

 Tissue repair
ns Apoptotic Angiogenesis
cell recognition Growth factors
Inflammation
and removal Prosurvival pathways
resolution
and repair
P
Homeostasis
CR Prevention of autoimmunity
B cells C C1q
R 4 6
2, CD fH C5a

T reg
5 9 b Helper T cell
C
3 CD iC3 C3a
C3 d
st 3

ce
Adaptive a, or CR differentiation

lls
C5 C
defense a 3dg T cells TH1>TH17 TH17>TH1
Activation/survival Polyclonal D59
DAF, C
Ab response response CD46 T cells
IgG Complement C3a, C5a
Autoimmunity Opsonization CD46, DA APC DC M'
h FcHR I,II,III F
FcHR Chemotaxis APC
C5a C
Interface - I1 I TCC lysis C5 5a C3a TLR
P I C5 b-8
Enhanced F, A or X in a ,9 Osteal tissue C5a activation
T ct b , C5 /C
activation and a m 2 C b 5 Synovial cells
F ro P- CD14 3a -8 a desA
phagocytosis Th AS a MBL C1 3a/ C ,9 rg
nt. M C5 TLR2 q desA
TLR4 C5a rg
Coagulation TLR9 C3a Bone marrow Cartilage and
bone resporation
Innate TLRs HSPC molbilization
Spread of DIC
s defense infection Immune cell
replenishment
and
Enhanced
inflammation Inflammatory Cell-dependent
antimicrobial
cytokine differential
functions
amplification regulation of
(phagocytosis,
IL-12 family
oxidative burst
and so on)

Ricklin D, Hajishengallis G, Yang K, Lambris JD.

n also be involved in immunopathology, such as FcHR-mediated autoimmunity, disseminated
Complement: a key systemintravascular
for immune surveillance and

El complemento homeostasis. Nat Immunol. 2010;11:785-797. Figure 3,

ion (for example, through sublytic C5b-9 signaling). The functional repertoire of complement includes the
Integrative role of complement in host defense and
egulatory T cells, noninflammatory clearance of apoptotic cells (which permit complement
homeostasis; p. 790. activation through
motion of tissue repair. Most complement interactions are bidirectional, in that the production and activation of
by other receptors or system components (for example, FcHRs, TLRs, thrombin).
Thursday, May 12, 2011
 BioVisions
The Inner Life of the Cell Harvard University

Thursday, May 12, 2011

 Next class: Tejidos y órganos linfoides

Paul WE. Fundamental Immunology. 6th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008.
Roitt IM, Brostoff J, Male DK. Immunology. 7th ed. Edinburgh ; New York: Mosby; 2009.
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby immunology. 6th ed. New York: W.H. Freeman; 2007.
Abbas AK, Lichtman AH. Cellular and molecular immunology. 5th ed. Philadelphia, PA: Saunders; 2005.

Thursday, May 12, 2011