Lymphatic System and ANTIBODIES (Abs) and complement system

Lymphatic System
 Within the body, there are two circulatory systems, the blood and the
lymph.
 Components of the blood that leave the vessels and enter the tissues
comprise the extracellular fluid.
 This fluid returns to the blood by draining into a network of vessels
called lymphatics.
 At the junction between major lymphatic vessels are small, bean-shaped,
discrete aggregates of tissue called lymph nodes.
 The lymphatic system includes the organs where lymphocyte maturation,
differentiation, and proliferation take place.
Primary and secondary lymphoid organs
What is lymph?
 Lymph means “clear water” and it is the colorless fluid and protein
that has been squeezed out of the blood.
 Lymph is a fluid similar in composition to blood plasma.
 Changes in plasma composition will change lymph composition.
 Protein concentration of lymph is lower than in plasma

1- The lymphoid organs include:
a-Primary lymphatic organs
- Thymus gland (T lymphocytes).
- Bursa equivalent tissues (B lymphocytes), which are the fetal liver and
bone marrow (in adult man).
i- The thymus gland:
- T-cell originate from the bone marrow (immature, pre-T cells) are
attracted to the thymus from the bone marrow by thymus hormones,
differentiate into mature T-cells released to populate the peripheral
lymphoid tissue.
ii- Bursa of Fabricius and bone marrow
- The bursa of Fabricius is a primary lymphoid tissue concerned with
the development and differentiation of B-cells.
- Birds which have this organ removed are not able to mount a normal
antibody response when stimulated with an antigen.
♦ In mammals, tissues resemble the bursa include the gut-associated
lymphoid tissues (GALT; including the appendix and Peyer’s patches), the
fetal liver and, following birth, the bone marrow.
♦ T- and B-lymphocytes develop in primary lymphoid organs.
b- Secondary lymphatic organs
1. Encapsulated lymphoid tissue includes the spleen and lymph nodes.
2. Unencapsulated diffuse lymphoid tissue includes gut-associated
lymphoid tissues (GALT) and tonsils.
• They are responsible for the production of mature, naїve (virgin),
lymphocytes.
• Their initial development maturation process is independent of antigen.
• Secondary lymphoid tissues allow the accumulation and presentation of
antigen to both naїve and memory lymphocyte populations.

♦ The secondary lymphoid organs have two major functions:
1- They are highly efficient in trapping and concentrating foreign substances.
2- They are the main sites of production of antigen specific antibodies and
the generation of antigen specific T-lymphocytes.
i-The spleen
- The spleen is a secondary lymphoid organ but also performs several
other non-immunological functions.
- The spleen is the major organ in the body in which antibodies are
synthesized and from which they are released into circulation.
ii-Lymph nodes
- The lymph nodes are highly organized lymphoid structure (as in figure)
that collect the extracellular fluid (the lymph) from tissues via
lymphatic vessels and returns it to the blood.
- The afferent lymphatic vessels which drain fluid from the tissues also
carry antigens from sites of infection in most parts of the body to the
lymph nodes, where they are trapped.

3- Tertiary lymphoid tissues
- They are very few in number but may undergo a rapid and substantial
increase during an immune response including the intraepithelial
lymphocytes (IEL) and the mucosa-associated lymphoid tissue.
ANTIBODIES (Abs)
♦ Immunoglobulin domains
 Antibodies are glycoproteins belonging to the immunoglobulin
superfamily.
 The terms antibody (Ab) and immunoglobulin (Ig) are often used
interchangeably.
 The Ig monomer is a "Y"-shaped molecule that consists of four
polypeptide chains two identical heavy chains and two identical light
chains connected by disulfide bonds produced by B-cells.
 They are used by the immune system to identify and neutralize foreign
objects such as bacteria and viruses.
 Immunoglobulin (Ig) domains consist of variable or IgV, and constant
or IgC.
 They are held together by interactions between cysteines and other
charged amino acids.
 The antibody recognizes a unique part of the foreign target, called an
antigen.

 Each tip of the "Y" of an antibody
contains a paratope (a structure
analogous to a lock) that is specific
for one particular epitope (similarly
analogous to a key) on an antigen,
allowing these two structures to bind
together with precision.
 The production of antibodies is the
main function of the humoral immune
system.
 Antibodies are secreted by a type of white blood cell called a plasma
cell (mature B cell).
♣ Antibodies can occur in two physical forms
i-A soluble form
 that is secreted from the cell, and released into the blood and tissue
fluids to survey for invading microorganisms.
ii-A membrane-bound form
 that is attached to the surface of a B cell and is referred to as the B- cell
receptors (BCR).
The BCR is only found on the surface of B cells and facilitates the
activation of these cells and their subsequent differentiation into either
antibody factories called plasma cells, or memory B- cells.
In most cases, interaction of the B cell with a T helper cell is necessary to
produce full activation of the B cell.
 Two large heavy (H) chains and two
small light (L) chains.
 There are several different types of
antibody heavy chains, and several
different kinds of antibodies, which are
grouped into different isotypes based on
which heavy chain they possess.

 There are five different antibody isotypes are known in mammals.
 Though the general structure of all antibodies is very similar, a small
region at the tip of the protein is extremely variable, allowing millions
of antibodies with slightly different tip structures, or antigen binding
sites, to exist.
 This region is known as the hypervariable region.
 Each of these variants can bind to a different antigen.
 This enormous diversity of antibodies allows the immune system to
recognize an equally wide variety of antigens.
A- Heavy chain
 There are five types of mammalian Ig Heavy chain denoted by the
Greek letters: α, δ, ε, γ, and μ.
 The type of heavy chain present defines the class of antibody; these
chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,
respectively.
 Distinct heavy chains differ in size and composition; α and γ contain
approximately 450 amino acids, while μ and ε have approximately 550
amino acids.
 Each heavy chain has two regions, the constant region (C) and the
variable region (V).
 The C region is identical in all antibodies of the same isotype, but
differs in antibodies of
different isotypes.
 Heavy chains γ, α and δ
have a constant region
composed of 3 tandem (in
a line) Ig domains, and a
hinge region for added
flexibility;
 Heavy chains μ and ε have
a constant region
composed of 4
immunoglobulin domains.

 The V region of the heavy chain is approximately 110 amino acids and
composed of a single Ig domain.
 It differs in antibodies produced by different B cells, but is the same for
all antibodies produced by a single B cell or B cell clone.
b- Light chain
 In mammals, there are 2 types of immunoglobulin light chain, which are
called lambda (λ) and kappa (κ).
 A light chain has 2 domains: one constant domain (CL) and one
variable domain (VL).
 It consists from 211 to 217 amino acids.
 Each antibody contains 2 light chains that are always identical; only one
type of light chain, κ or λ.
 Fragment, crystallizable (Fc) region, it composed of two heavy chains
and ensures that each antibody generates an appropriate immune
response for a given antigen, by binding to a specific class of Fc
receptors, and other immune molecules, such as complement proteins.
 Fc region, composed of two heavy chains that contribute two (γ,α,δ) or
three (μ, ε) constant domains depending on the class of the antibody.
 So, Fc region mediates different physiological effects including
recognition of opsonized Ag.
 Activated B cells differentiate it into either antibody-producing cells
called plasma cells that
secrete soluble antibody
or memory cells that
survive in the body for
years.
 Memory cells allow the
immune system to
remember an antigen
and respond faster upon
re-exposure.

Elucidation of Igs chemical structure

 At the prenatal and neonatal stages of life, the presence of antibodies
is provided by passive immunization from the mother.
 Early endogenous antibody production varies for different kinds of
antibodies, and usually appears within the first years of life.
 Since antibodies exist freely in the bloodstream, they are said to be part
of the humoral immune system.
 Circulating antibodies are produced by clonal B cells that specifically
respond to only one antigen (e.g. is a virus capsid protein fragment).

Antibodies are typically made of basic structural units.
◘ Antibodies contribute to immunity in 3 ways:
a) Antibodies prevent pathogens from entering or damaging cells by binding
to them.
b) Antibodies stimulate removal of pathogens by macrophages and other
cells by coating the pathogen (opsonization).
c) Antibodies trigger destruction of pathogens by stimulating other immune
responses such as the complement pathways.
♣ Activation of complement (C):
 Antibodies that bind to surface antigens, e.g. a bacterium, attract the
first component of the complement (C) cascade (C1) with their Fc
region and initiate activation of the "classical" complement system.

♦ This results in the killing of bacteria in two ways:
a- Opsonization: the binding of the antibody and complement molecules
marks the microbe for ingestion by phagocytes in a process called
opsonization; these phagocytes are attracted by certain complement
molecules generated in the complement cascade.
b- Membrane attack complex (MAC): some complement system
components form a membrane attack complex (MAC) to assist
antibodies to kill the bacterium directly.
♣ Activation of effector cells
 To fight pathogens that replicate outside cells, antibodies (Ab) bind to
pathogens to link them together, causing them to clump (agglutinate).
 Since an antibody has at least two paratopes it can bind more than one
antigen by binding identical epitopes carried on the surfaces of these
antigens.
 By coating the pathogen, antibodies stimulate effector functions against
the pathogen in cells that recognize their Fc region.
 The first secreted mammalian IgM has five Ig units (monomer).
 Each Ig unit has two epitope binding Fab regions, so IgM is capable of
binding up to 10 epitopes.
♣ The engagement of a particular antibody IgA, IgG and IgE with the Fc
receptor on a particular cell triggers an effector function of that cell:
a- Phagocytes will phagocytose.
b- Mast cells and neutrophils will degranulate mediators.
c- Natural killer(NK)cells will release cytokines and cytotoxic
molecules.
 This will ultimately result in destruction of the invading microbe.
 The Fc receptors are isotype-specific, which gives greater flexibility to
the immune system.

♦ Class switching
 Isotype or class switching is a biological
process occurring after activation of the
B-cell, which allows the cell to produce
different classes of antibody (IgA, IgE,
IgG).
 The different classes of antibody, and thus
effector functions, are defined by the
constant (C) regions of the immunoglobulin H chain.
 Initially, naïve B-cells express only cell-surface IgM and IgD with
identical antigen binding regions.
 Each isotype is adapted for a distinct function, therefore, after
activation, an antibody with a IgG, IgA, or IgE effector function might
be required to effectively eliminate an antigen.
 Only the constant region of the antibody heavy chain changes during
class switching; the variable regions, and therefore antigen specificity,
remain unchanged.
 Thus the progeny of a single B- cell can produce antibodies, all specific
for the same antigen, but with the ability to produce the effector
function appropriate for each antigenic challenge.
 Cytokines trigger class switching.
♣ Natural antibodies
 Definition: Natural antibodies are antibodies that are produced without
any previous infection, vaccination, other foreign antigen exposure or
passive immunization.
 Natural antibodies produce by humans and higher primates.
 These antibodies can activate the classical complement pathway
leading to lysis of enveloped virus particles long before the adaptive
immune response is activated.
 Rejection of xenotransplanted organs is thought to be, in part, the
result of natural antibodies circulating in the serum of the recipient.

◘ Immunoglobulin diversity
 Successful recognition and eradication of many different types of
microbes requires diversity among antibodies; their amino acid
composition varies allowing them to interact with many different
antigens.
 It has been estimated that humans generate about 10 billion different
antibodies, each capable of binding a distinct epitope of an antigen.
 Although the number of genes available to make these proteins is
limited by the size of the human genome.
♣ Definitions:
 Monoclonal antibodies (mAb) are antibodies that are identical because
they were produced by one type of immune cell (B cell), all clones of a
single parent cell.
 Polyclonal antibodies are antibodies that are derived from different cell
lines.
♣ Chemical basis of Ag-Ab interaction
 When Ag and its specific Ab come close to each other they interact
through the chemical groups on the surface of the epitope and the
paratope.
 The major bond between them is exclusively hydrophobic
monovalent.

◘ The main features of Ag-AB reactions:
1-Specificity:
 like lock and key mechanisms, the interaction between Ag and
Ab is highly specific.
2-Antibody avidity:
 the overall strength of an Ab binding to multivalent
Ag is known as avidity.
 Avidity is influenced by valency of both Ab and Ag.
3-Cross reactivity:
 there is a possibility of presence of similar
epitopes on different Ags.
 So, Abs produced for a specific Ag can cross
react with Ags having similar epitopes.
4-Antigen precipitation:
 Soluble Ag molecule enables Abs to neutralize, opsonize and inactivate
toxic substances and pathogens.
 Ag with 2 or more epitopes is essential to produce precipitation reaction
in polyclonal antiserum.
5-Bonus effect:
 Ag with multivalent or multiple epitopes can react with different Abs.
 If Ag is bridged by 2 or more Abs the binding strength of Ag-Ab
increases (bonus effect).
 The increased valency of an Ag and the presence of polyclonal Abs
enhance the bonus effect.
6-Neutralization of toxins:
 Toxins are Ags which induce Abs production.
 Binding of these Ags shield the toxic sites of toxins causing
neutralization.

Ͽ Primary and Secondary Immune Response
 The time course of an immune response.
 Due to the formation of immunological memory, re-infection at later
time points leads to a rapid increase in antibody production and effector
T cell activity.
 These later infections can be mild or even in apparent.

♣ Complement © System Definition :
 Series of ~ 20 heat-labile serum proteins (enzymes), discovered by Jules
Borde, inactivated by heating at 56 0
C.
 Site : serum and all tissue fluids except urine and cerebrospinal fluid
(CSF).
 Synthesis : in liver – appear in fetal circulation during 1st 13week
 Function : Responsible for certain aspects of immune response and
inflammatory response.
 Activation : activated directly by pathogens or indirectly by pathogen-
bound antibody, leading to a cascade of reactions that occurs on the
surface of pathogens and generates active components with various
effector functions.
 Inactivation: inhibitors in plasma (short lived).
 Biological effects: either beneficial or harmful to host.
 Complement account for about 5% of the globulin fraction of blood
serum (3g/L), normally circulating as inactive precursors (pro-proteins).
 The complement (C) system helps or complements the ability of
antibodies and phagocytic cells to clear pathogens from an organism.
 It is part of the innate immune system and adaptive immune system.
- The proteins in this pathway are named C1q, C1r, C1s, C2-9,
- Factor B, Factor D,
- Properdin,
- Regulatory proteins (C1-inhibitor, Factor I, C4bBP, Factor H, S
protein, anaphylatoxin inactivator).
◘ Activated complement cause:
1- Recruitment of inflammatory cells, 2-Killing of pathogen,
3- Opsonization of pathogens (attaching of complement to microbial surfaces
to target the microbes for phagocytosis).

♣There are three biochemical pathways activate the complement
system:
a) The classical complement pathway,
b) The alternative complement pathway,
c) The lectin pathway.
I-The Complement reaction passes through three stages:
1- activation
2- amplification
3- killing

A-The classical complement pathway:
1- Activation
- C1 comprises three different types of molecule
– C1q, C1r and C1s – which, in the presence
of calcium, are held together.
a- C1q portion of C1 attaches to the Fc portion of an
antibody.
b- Only IgG 1,2,3 and IgM can activate complement.
c- Once activated C1s is eventually cleaved which activates C4 and C2.
d- C4b & C2a come together to form the C4b2a which is the C3 convertase
e- C3 convertase activates C3 splitting it to C3a and C3b.
- C3a binds to receptors on basophils and mast cells triggering them to
release there vasoactive compounds (enhances vasodilation and
vasopermeability), C3a and C5a are called an anaphylatoxin.
- C3b and C4b serve as an opsonin which facilitates immune complex
clearance.

2-Amplification:
a- Each C1s creates 100 C4b and C2b fragments.
b- 100 C4bC2a creates 10,000 C3b (activated C3).
c- 10,000 C3b goes on to create 1,000,000
Membrane Attack Complexes (MAC).
3-Attack:
– Most C3b serves an opsonin function.
– Some C3b binds to C4bC2a to form the C5 convertase C4bC2aC3b.
– C5 convertase cleaves C5 leading to the formation of the Membrane
attack Complex MAC (C5-C6-C7-C8-C9).
– The MAC ―punches holes in cell walls resulting in lysis.
B-Alternative Complement pathway:
1- Activation:
- Spontaneous conversion from C3 to C3b occurs in body
- Normally, C3b is very short lived and quickly inactivated by proteins
on the surface of the body’s own cell membranes.
- However, bacteria or other foreign material may lack these surface
proteins allowing C3b to bind and stay active.
2- Amplification
 Factor B binds to C3b.
 Factor B is then cleaved by factor D into Ba and Bb.
 C3bBb acts as a C3 convertase (converts C3 C3a and C3b).
 C3bBbC3b is formed which acts as a C5 convertase.
– C5 is cleaved to C5a and C5b.
– C5b then starts the assembly of the
MAC.
♣ C-Lectin pathway:
 The lectin pathway is homologous to the
classical pathway, but requires mannose-
binding lectin (MBL) and ficolins on
microorganisms.

◘ Functions of the complement system members:
 C3a, C5a: anaphylatoxins (= they cause release of histamine and other
vasoactive compounds from basophils and mast cells, increasing
capillary permeability).
 C3b, C4b: opsonization (they bind IC to macrophages and neutrophils,
enhancing phagocytosis; also binds complexes to erythrocytes,
facilitating removal by the liver and spleen).
 C5a: chemotaxis (attracts phagocytic cells to sites of inflammation and
increases their overall activity).
 C5b,C6,C7,C8, C9 : components of MAC.
 Ba: neutrophil chemotaxis.
 Bb: macrophage activation.
♣ Some Regulations of Complement system
 C1 inhibitor : serine proteinase inhibitor (aka serprin) – binds and
inactivates C1r and C1s
 Inhibition of formation of C3 convertase enzyme- C4b2a, by
ongoing catabolization of C4b by Factor I and C4 binding protein.
‫ال‬diagrams‫حاطاها‬ ‫انا‬ ‫زياده‬ ‫كدا‬ ‫غير‬ ‫علينا‬ ‫اللي‬ ‫بس‬ ‫هي‬ ‫اسود‬ ‫بإطار‬ ‫متحدده‬ ‫اللي‬ ‫والصور‬
‫للتوضيح‬♥

Lymphatic System and ANTIBODIES (Abs) and complement system

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