III. Complement
The components of immune system
Leukocytes
Lymphoid organs
Cytokines
Janeway et al. Immunobiology, 5th edn.
Bone marrow
Bone marrow
Give rise to
produce
Blood
Leukocytes
Lymphoid organs
Cytokines
Tissues involved in the immune system (lymphoid organs):
* *
*
Ag/DC
Leukocytes
Lymphoid organs
Cytokines
The Role of Cytokines in Immune Response
• Stimulators of hematopoiesis
-produced by bone marrow stromal cells, leukocytes,
and other cells
(stem cell factor, GM-CSF, IL-3, IL5, IL-7, homeostatic chemokines)
IL-2 IL-1
Juxtacrine
TNF-α
IL-6 Endocrine
STATs:
Signal Transducers and
Activators of Transcription
Inflammatory Chemokines
•Are expressed in inflamed tissues by resident and
infiltrated cells upon stimulation by proinflammatory
cytokines or during contact with pathogenic agents.
•Are specialized for the recruitment of effector cells,
including monocytes, granulocytes and effector T cells.
Recruitment of Leukocytes to Inflammatory Sites by Chemokines
Cell 76:301,1994
The components of immune system
Leukocytes
Lymphoid organs
Cytokines
Routes of Antigen Entry
Phagocytic cells
PAMP PRR
TLR3
TLR4
TLR9
GPCR
PAMP
Plasma membrane
PRR
Endosomal membrane
Humoral immunity
•mediated by antibodies that are produced by B cells
•the principal defense mechanism against extracellular
microbes and their toxin
Cell-mediated immunity
•mediated by T lymphocytes
•Defense against intracellular microbes
Types of Adaptive Immunity
Humoral Cell-mediated
immunity immunity
V = 45
D = 23
J=6
VxDxJ=6210
V = 35
J=5
VxJ=175
V = 30
J=4
V x J =120
1. Digest DNA from early embryo or from MOPC 321 plasmacytoma with BamH I
2. Fractionate resulting DNA fragments by gel electrophoresis
3. Hybridize gel-extracted DNA with 125I-labeled,
whole κ-mRNA of MOPC 321 or its 3’-end half fragment
3.9x106
Hozumi and Tonegawa Proc. Natl. Acad. Sci. 73: 3628, 1976
Somatic rearrangement
κ Light chain
BamH I BamH I BamH I
Germline DNA
3.9x106
6x106
Somatic recombination
V-J joining
B-cell DNA
3’-half probe 2.4x106
Whole probe
Diversity of antigen receptor genes
Effector function
V: variable
C: constant
H: heavy chain
L: light chain
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Cell-mediated Immunity
Routes of Antigen Entry
Molecules involved:
T cells : TCR, accessory molecules (CD4, CD8, CD28)
Antigen presenting cells: major histocompatibility
complex (MHC), accessory molecules (B7, CTLA-4)
ITAMs
Immunoreceptor
tyrosine-based
activation motifs
β-pleated sheet
MHC Restriction
(MHC-restricted antigen recognition)
MHC restriction
T cells from any one individual recognize foreign peptide antigens only when these
peptides are bound to and displayed by the MHC molecules of that individual.
Naïve T clles
Isolated lymphocytes
TCR-peptide-MHC
complex
CD28
Cross-linking of CD28 delivers the co-stimulatory signal during activation CTLA-4 binds B7 more avidity than does CD28 and
of naïve T cells and induces the expression of CTLA-4 delivers inhibitory signals to activated T cells
Th1 cells
Th2 cells
Perforing and
granzymes
Cells involved-
B cells (B1; B2; Marginal zone B cells)-recognition of antigens by BCR
Helper T cells- direct contact with B cells and provide secondary signal
(Thymus –dependent antigens; TD Ag); secretion of cytokines
(TD Ag and Thymus-independent antigens; TI Ag)
Phagocytic cells (macrophages and neutrophils)-effector functions
Major molecules involved-
Antibodies (IgM, IgG, IgA, IgE): recognition of antigen;
activation of complement cascade; activation of phagocytic cells
Cytokines: B cell growth/differentiation factors IL-4, IL-5, IL-6, CD40L,etc.
Complement and complement receptor (CR): opsonization (C3b);
chemotaxis (C5a); membrane-attack complex (C5-9); activation of
phagocytic cells; removal of immune complex
Fc receptors: activation of phagocytic cells, natural killer cells
Effector function
Effector function
V: variable
C: constant
H: heavy chain
L: light chain
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Fc receptors (effector function)
ADCC
Ag-Ab
complex
Complement activation
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Regulation of B cell Activation by Ig Fc Receptors
Fab
FcγRIIB
ITIM
There are three ways that complement can recognize the microbes:
• The classical pathway: recognize antibody-bounded microbe
• The alternative pathway: direct recognize certain microbial surface structures
• The lectin pathway: triggered by a plasma protein called mannose-binding
lectin, which recognize terminal mannose residues on microbial
glycoproteins and glycolipids.
Pathways of Complement Activation
C5b6789
Abbas and Lichtman, Cellular and Molecular Immunology, 5th edn.
Physiological Regulation of the Complement Cascade
Activation of Complement Pathways
C5b6789
ADCC
C5b6789
C5b
C5a