Introduction to cellular basis of Immunity

Introduction
Immunity is derived from a Latin word “ immunitas” which means “exempt” which is state of protection

from infectious disease. Immunity generally means protection. In biological terminology, immunity is the

natural process that is responsible for fighting microorganisms, which enter our bodies to damage the

cells. Basically, when our body detects a pathogen, our immune system gets activated. Pathogens are the

microorganisms that are either bacteria or viruses, which are capable of causing a disease.

So, immunity, is a natural process which keeps us safe from minor and major ailments. We all know that

ailments are inevitable whatsoever but can we even guess the number of times our body escapes

infections? How many times our body fights bacteria and viruses without even letting us know? Our

immunity system is our Superman inside who saves us from diseases.

Organs of Immune system

The organs of the immune system, the lymphoid organs, are distributed throughout the body. They can be

divided into primary lymphoid organs, where the lymphocytes—the central actors of the immune

system—are generated, and secondary lymphoid organs, where the adaptive immune responses are

initiated. The primary organs are the bone marrow and the thymus, whereas the secondary organs

(also called the peripheral lymphoid organs) are the lymph nodes, spleen and the mucosal- and gut-

associated lymphoid tissues (MALT and GALT, respectively), i.e. tonsils, adenoids, the appendix and

the Peyer’s patches of the small intestine (Fig 1).

Before knowing the details of immune cells, we should first recall the types of blood cells human body

has; these are Red blood corpuscles (RBCs), blood platelets and White blood corpuscles (WBCs) or

leucocytes. So, RBCs are involved in oxygen transport and blood platelets are the cells take part in blood

clotting. WBCs or leucocytes are the cells which constitute the defense system of our body. It protects us

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from foreign microbes and infections. They are granulocytes (granule bearing cells, neutrophils, basophils

and eosinophils) and agranulocytes (without granules in cell cytoplasm, monocytes and lymphocytes)

(Fig 2).

Fig. 1 showing organs of immune system

Fig. 2 showing types of leucocytes

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 Classification Immunity can be classified into two types: Innate and Adaptive Immunity

(i) Innate Immunity (natural/ non-specific/ present by birth)

Innate immunity represents the first line of host defense against pathogenic micro-organisms that have

entered the body. This innate defense mechanism lacks memory and is mostly focused on a limited set of

microbial determinants shared by a large number of pathogens. Innate responses are characterized by a

lack of learning process and rapid kinetic, providing almost immediate protection against invading

pathogens. It is non-specific and comprises four types of defensive barriers. Skin itself is a part of innate

immunity as physical barrier. It is the primary defense of body that stops harmful organisms from

entering the body. However, pathogens can still break into the body by means of air, food or water. The

second defense of the body is in the form of mucus which attaches the pathogen to itself and kills it right

there. It is destroyed by the complement system which involves a set of proteins.

Now let’s assume the pathogen is even more powerful and it escapes from skin and then mucus as well.

It further goes inside and confronts the cells called phagocytes and NK cells. Phagocytes are of three

types: Macrophages, Neutrophils and Dendritic cells

All these cells detect the pathogen, attack and destroy it right there by a process called phagocytosis.

The body sends a whole army of cells to fight the pathogen. NK stands for natural killer cells. These

cells on the other hand fix the damage already caused to the host cells. It kills them so the pathogen is

finally eradicated from the body. If the pathogen still survives phagocytes and NK cells, then our body

activates the secondary immunity which is the adaptive immunity.

(ii) Adaptive Immunity (Acquired/specific)

It is the functional immune system and capable of recognizing and selectively eliminating foreign

microorganisms and molecules. Adaptive immunity provides a second line of defense, often at a later

stage of infection. Adaptive immunity is relatively slower as compared to innate immunity. Adaptive

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responses are characterized by a very large set of effector molecules and cells, able to efficiently

recognize and eliminate virtually any known pathogen. After elimination of the pathogen, the adaptive

immune response establishes a state of “memory” characterized by the ability to efficiently protect the

body from re-infection with the same agent. Memory is the hallmark of the adaptive immune response

and can be induced by both natural infection and vaccination.

Our immune system produces proteins known as antibodies. They neutralize the pathogen There are two

kinds of adaptive immunity, active and passive. The active immunity works by means of two kinds of

cells: B lymphocytes and T lymphocytes where antibodies are produced in response to pathogen and

memory cells are generated which remember the earlier exposure of the pathogen nd again ready to

secrete antibodies. Passive immunity on the other hand involves the transfer/injection of antibodies

which are acquired from another person.

Cells of adaptive Immunity

B and T lymphocytes which are derived from specific types of stem cells, called multipotent

hematopoietic stem cells, in the bone marrow. After they are made in the bone marrow, they need to

mature and become activated. Each type of cell follows different paths to their final, mature forms.

B Lymphocytes After formation and maturation in the bone marrow (hence the name “B cell”), the

naive B cells move into the lymphatic system to circulate throughout the body. In the lymphatic system,

naive B cells encounter an antigen, which starts the maturation process for the B cell. B cells each have

one of millions of distinctive surface antigen-specific receptors that are inherent to the organism’s DNA.

For example, naive B cells express antibodies on their cell surface, which can also be called membrane-

bound antibodies.

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B cell and membrane-bound antibodies When a naive B cell encounters an antigen that fits or matches

its membrane-bound antibody, it quickly divides in order to become either a memory B cell or an effector

B cell, which is also called a plasma cell. Antibodies can bind to antigens directly. The antigen must

effectively bind with a naive B cell’s membrane-bound antibody in order to set off differentiation, or the

process of becoming one of the new forms of a B cell.

A B

Fig: 3 (A) Surface bound antibodies on naïve B cells; (B) membrane bound antibodies and its interaction with antigen

Memory B cells express the same membrane-bound antibody as the original naive B cell, or the “parent B

cell”. Plasma B cells produce the same antibody as the parent B cell, but they aren’t membrane bound.

Instead, plasma B cells can secrete antibodies. Secreted antibodies work to identify free pathogens that

are circulating throughout the body. When the naive B cell divides and differentiates, both plasma cells

and memory B cells are made. B cells also express a specialized receptor, called the B cell receptor

(BCR). B cell receptors assist with antigen binding, as well as internalization and processing of the

antigen. B cell receptors also play an important role in signaling pathways.

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T cells

Once formed in the bone marrow, T cell progenitors migrate to the thymus (hence the name “T cell”) to

mature and become T cells. While in the thymus, the developing T cells start to express T cell receptors

(TCRs) and other receptors called CD4 and CD8 receptors. All T cells express T cell receptors, and either

CD4 or CD8, not both. So, some T cells will express CD4, and others will express CD8. Unlike

antibodies, which can bind to antigens directly, T cells (receptors) can only recognize antigens when they

are bound with Major Histocompatibility Complex class 1 (MHCI) and class 2 (MHCII). MHC class

2 are membrane-bound surface receptors on antigen-presenting cells, like macrophages, B cells and

dendritic cells. CD4 and CD8 play a role in T cell recognition and activation by binding to either MHCI

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or MHCII. MHC I glycoproteins are present on cell membranes of all the nucleated cells whereas

MHCII are present only on antigen presenting cells(APCs).

There are three types of T cells: Helper T cells (TH), Cytotoxic T cells (TCyt) and T regulatory cells (T

reg). Helper T cells express CD4, and help with the activation of B cells, and other immune cells.

Cytotoxic T cells express CD8, and are responsible for removing pathogens and infected host cells.

T regulatory cells express CD4 and another receptor, called CD25. T regulatory cells help distinguish

between self and non-self molecules, and by doing so, reduce the risk of autoimmune diseases.

Humoral and Cell Mediated Immunity

There are two types of immunity that the adaptive immune system provides, and they are dependent on

the functions of B and T cells, as described above. Humoral immunity is immunity from serum

antibodies produced by plasma cells (effector B cells). More specifically, someone who has never been

exposed to a specific disease can gain humoral immunity through administration of antibodies from

someone who has been exposed, and survived the same disease (this is a type of passive immunity

because antibodies are transferred from some other individual). “Humoral” refers to the bodily fluids

where these free-floating serum antibodies bind to antigens and assist with elimination.

Cell-mediated immunity can be acquired through T cells from someone who is immune to the target

disease or infection. “Cell-mediated” refers to the fact that the response is carried out by cytotoxic cells.

Much like humoral immunity, someone who has not been exposed to a specific disease can gain cell-

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mediated immunity through the administration of TH cells and Tcyt cells from someone that has been

exposed, and survived the same disease. The TH cells act to activate other immune cells, while the Tcyt

cells assist with the elimination of pathogens and infected host cells.

Immunological memory

Because the adaptive immune system can learn and remember specific pathogens, it can provide long-

lasting defense and protection against recurrent infections. When the adaptive immune system is exposed

to a new threat, the specifics of the antigen are memorized so we are prevented from getting the disease

again. The concept of immune memory is due to the body’s ability to make antibodies against different

pathogens.

A good example of immunological memory is shown in vaccinations. A vaccination against a virus can

be made using either active, but weakened or attenuated virus, or using specific parts of the virus that are

not active. Both attenuated whole virus and virus particles cannot actually cause an active infection.

Instead, they mimic the presence of an active virus in order to cause an immune response, even though

there are no real threats present. By getting a vaccination, you are exposing your body to the antigen

required to produce antibodies specific to that virus, and acquire a memory of the virus, without

experiencing illness.

Some breakdowns in the immunological memory system can lead to autoimmune diseases. Molecular

mimicry of a self‐antigen by an infectious pathogen, such as bacteria and viruses, may trigger

autoimmune disease due to a cross-reactive immune response against the infection. One example of an

organism that uses molecular mimicry to hide from immunological defenses is Streptococcus infection.

Innate Immunity vs. Adaptive Immunity: A summary

The following chart compares and summarizes all of the important parts of each immune system:

Quality Innate Immunity Adaptive Immunity

Response Time Fast: minutes or hours Slow: days

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 Quality Innate Immunity Adaptive Immunity

Only specific for molecules and Highly specific! Can discriminate between
molecular patterns associated with pathogen vs. non-pathogen structures, and
general pathogens or foreign miniscule differences in molecular
Specificity particles structures

Macrophages, Neutrophils, Natural

Killer Cells, Dendritic Cells, T cells, B cells, and other antigen
Major Cell Types Basophils, Eosinophils presenting cells

Antimicrobial peptides and proteins,

Key Components such as toxic granules Antibodies

Not as good as the innate immune system,

but still pretty good at determining which is
Innate immunity is based on self vs. which. Problems in self vs. nonself
Self vs. Nonself nonself discrimination, so it has to be discrimination result in autoimmune
Discrimination perfect diseases

Immunological Memory used can lead to faster response to

Memory None recurrent or subsequent infections

Limited: Receptors used are standard

and only recognize antigen patterns. Highly diverse: can be customized by
Diversity and No new receptors are made to adapt genetic recombination to recognize
Customization the immune response epitopes and antigenic determinants.

III. BASIC STRUCTURE OF IMMUNOGLOBULINS

A. An antibody is composed of two heavy chains (50 KD each) and two light chains (25 KD each),
which are joined by disulfide bonds to form a ‘Y’ shaped structure (150 KD). Antibodies are
further divided into two regions: a variable region and a constant region.

B. The variable region is responsible for the antigenic specificity of an antibody. This region
includes a fragment antigen binding (Fab) portion that binds the antigen with high specificity.

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 There are two Fab portions in each antibody, which can simultaneously bind two identical
epitopes (a specific antibody-binding site of an antigen) of a particular antigen.

C. The constant region of an antibody includes a fragment crystallization (Fc) portion that binds cell
surface receptors (Fc receptors) on circulating WBCs, macrophages, and natural killer cells. This
binding is necessary to initiate an immune reaction. In addition, there are two hinge regions that
join the Fab and Fc portions of an antibody.

Fig 4 Antibody structure

GENERAL FUNCTIONS OF IMMUNOGLOBULINS

(a)Antigen binding Immunoglobulins bind specifically to one or a few closely related antigens. Each
immunoglobulin actually binds to a specific antigenic determinant. Antigen binding by antibodies is the
primary function of antibodies and can result in protection of the host. The valency of antibody refers to
the number of antigenic determinants that an individual antibody molecule can bind. The valency of all
antibodies is at least two and in some instances more.

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b. Effector functions Frequently the binding of an antibody to an antigen has no direct biological effect.
Rather, the significant biological effects are a consequence of secondary "effector functions" of
antibodies. The immunoglobulins mediate a variety of these effector functions. Usually the ability to carry
out a particular effector function requires that the antibody bind to its antigen. Not every immunoglobulin
will mediate all effector functions. Such effector functions include:

1. Fixation of complement - This results in lysis of cells and release of biologically active molecules.
2. Binding to various cell types - Phagocytic cells, lymphocytes, platelets, mast cells, and basophils have
receptors that bind immunoglobulins. This binding can activate the cells to perform some function. Some
immunoglobulins also bind to receptors on placental trophoblasts, which results in transfer of the
immunoglobulin across the placenta. As a result, the transferred maternal antibodies provide immunity to
the fetus and new born baby.

Types of antibodies
IgG
This isoform accounts for 70–75% of all human immunoglobulins found in the blood. Depending on the
size of the hinge region, the position of disulfide bonds, and the molecular weight of the antibody, IgG
can be further divided into 4 subclasses: IgG1, IgG2, IgG3, and IgG4.

In general, proteins are responsible for triggering IgG1 and IgG3 production, whereas IgG2 and IgG4
typically respond to foreign polysaccharides. IgG is the main component of the humoral immune system
(immune response initiated by macromolecules present in the extracellular fluid) because of its
abundance.

Due to its small size (monomeric) and high diffusibility, IgG is the prevalent type in the extracellular fluid
that binds Fc receptors on phagocytic or other lytic cells and initiates the antibody-dependent cell-
mediated cytotoxicity (ADCC) response – a cell-mediated defense mechanism wherein effector cells
(phagocytes) destroy the target cell.

In addition, IgG triggers phagocytosis to initiate opsonization reaction – a process used to destroy foreign
particles (e.g. bacteria) through phagocytosis. Apart from these functions, IgG is the only antibody that
can cross the placenta and provides passive immunity to the fetus and infants in the first few
months of life.

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IgM

IgM is the largest antibody and the first one to be synthesized in response to an antigen or microbe,
accounting for 5% of all immunoglobulins present in the blood. IgM typically exists as polymers of
identical subunits, with a pentameric form as the prevalent one.

In its pentameric form, five basic antibody units are attached by disulfide bonds. Other forms include
secretory IgM, which is synthesized by glandular-associated B cells, and monomeric form, which is
present in the B cell membrane and functions as a B cell antigen receptor.

Due to its large size, IgM is mostly intravascular and has a lower affinity for antigens. However, since
pentameric IgM has 10 antigen binding sites, it has higher avidity (overall binding strength) for antigens
than IgG and acts as an excellent activator of the complement system and agglutination.

IgA

It accounts for 10–15% of all immunoglobulins and is prevalent in serum, nasal mucus, saliva, breast
milk, and intestinal fluid. It has two subtypes namely IgA1 and IgA2, which mainly differ in terms of
their hinge region characteristics. At mucosal surfaces, IgA provides the primary defense against inhaled
and ingested pathogens.

IgE

IgE is the least prevalent one, with a serum concentration 10,000 times lower than IgG. However, the
concentration of IgE increases significantly in allergic conditions, such as bronchopulmonary
aspergillosis, and parasitic diseases, such as schistosomiasis.

In response to pathogens, IgE binds to mast cells via specific receptors, followed by pathogen-mediated
cross-linking of these receptors (degranulation). This causes recruitment of eosinophil at the site of
infection and destruction of pathogens via ADCC-type mechanisms.

IgD

IgD functions as a B cell antigen receptor and may participate in B cell maturation, maintenance,
activation, and silencing. Although the exact function is still unclear, IgD may be involved in humoral
immune responses by regulating B cell selection and homeostasis.

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S.no Immunoglobulin Heavy
type
chain

1. IgG Gamma (γ)

2. IgM Mu (µ)

3. IgA Alpha (α)

4. IgD Delta(δ)

5. IgE Epsilon(ε)

References:

1. Elements of Immunology by Fahim Halim Khan.

2. Immunology by Kuby.

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