(This journal article briefly presents the basics of immunology and immunopathology.

An Introduction to Immunology and Immunopathology

Warrington et al; Allergy, Asthma & Clinical Immunology. 10 November 2011

Abstract
In basic terms, the immune system has two lines of defense: innate immunity and adaptive immunity.
Innate immunity is the first immunological, non-specific (antigen-independent) mechanism for fighting
against an intruding pathogen. It is a rapid immune response, occurring within minutes or hours after
aggression, that has no immunologic memory. Adaptive immunity, on the other hand, is antigen-
dependent and antigen-specific; it has the capacity for memory, which enables the host to mount a more
rapid and efficient immune response upon subsequent exposure to the antigen. There is a great deal of
synergy between the adaptive immune system and its innate counterpart, and defects in either system can
provoke illness or disease, such as autoimmune diseases, immunodeficiency disorders and
hypersensitivity reactions. This article provides a practical overview of innate and adaptive immunity, and
describes how these host defense mechanisms are involved in both health and illness.

Introduction
Over the past decade, there have been numerous advances in our current understanding of the immune
system and how it functions to protect the body from infection. Given the complex nature of this subject,
it is beyond the scope of this article to provide an in-depth review of all aspects of immunology. Rather,
the purpose of this article is to provide medical students, medical residents, primary-care practitioners and
other healthcare professionals with a basic introduction to the main components and function of the
immune system and its role in both health and disease. This article will also serve as a backgrounder to
the immunopathological disorders discussed in the remainder of this supplement. The topics covered in
this introductory article include: innate and acquired immunity, passive and active immunization and
immunopathologies, such as hypersensitivity reactions, autoimmunity and immunodeficiency.

The immune system: innate and adaptive immunity

The immune system refers to a collection of cells and proteins that function to protect the skin, respiratory
passages, intestinal tract and other areas from foreign antigens, such as microbes (organisms such as
bacteria, fungi, and parasites), viruses, cancer cells, and toxins. The immune system can be simplistically
viewed as having two “lines of defense”: innate immunity and adaptive immunity. Innate immunity
represents the first line of defense to an intruding pathogen. It is an antigen-independent (non-specific)
defense mechanism that is used by the host immediately or within hours of encountering an antigen. The
innate immune response has no immunologic memory and, therefore, it is unable to recognize or
“memorize” the same pathogen should the body be exposed to it in the future. Adaptive immunity, on the
other hand, is antigen-dependent and antigen-specific and, therefore, involves a lag time between
exposure to the antigen and maximal response. The hallmark of adaptive immunity is the capacity for
memory which enables the host to mount a more rapid and efficient immune response upon subsequent
exposure to the antigen. Innate and adaptive immunity are not mutually exclusive mechanisms of host
defense, but rather are complementary, with defects in either system resulting in host vulnerability [1–3].

Innate immunity
The primary function of innate immunity is the recruitment of immune cells to sites of infection and
inflammation through the production of cytokines (small proteins involved in cell-cell communication).
Cytokine production leads to the release of antibodies and other proteins and glycoproteins which activate
the complement system, a biochemical cascade that functions to identify and opsonize (coat) foreign
antigens, rendering them susceptible to phagocytosis (process by which cells engulf microbes and remove
cell debris). The innate immune response also promotes clearance of dead cells or antibody complexes
and removes foreign substances present in organs, tissues, blood and lymph. It can also activate the
adaptive immune response through a process known as antigen presentation (discussed later) [1, 3].

Numerous cells are involved in the innate immune response such as phagocytes (macrophages and
neutrophils), dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells and lymphocytes
(T cells). Phagocytes are sub-divided into two main cell types: neutrophils and macrophages. Both of
these cells share a similar function: to engulf (phagocytose) microbes. In addition to their phagocytic
properties, neutrophils contain granules that, when released, assist in the elimination of pathogenic
microbes. Unlike neutrophils (which are short-lived cells), macrophages are long-lived cells that not only
play a role in phagocytosis, but are also involved in antigen presentation to T cells. Macrophages are
named according to the tissue in which they reside. For example, macrophages present in the liver are
called Kupffer cells while those present in the connective tissue are termed histiocytes (see Figure 1) [1].

Figure 1. Characteristics and function of cells involved in innate immunity [1, 3, 4]. *Dust cells (within
pulmonary alveolus), histiocytes (connective tissue), Kupffer cells (liver), microglial cells (neural tissue),
epithelioid cells (granulomas), osteoclasts (bone), mesangial cells (kidney)

Dendritic cells also phagocytose and function as antigen-presenting cells (APCs) and act as important
messengers between innate and adaptive immunity. Mast cells and basophils share many salient features
with each other and both are instrumental in the initiation of acute inflammatory responses, such as those
seen in allergy and asthma. Unlike mast cells, which generally reside in the connective tissue surrounding
blood vessels, basophils reside in the circulation. Eosinophils are granulocytes that possess phagocytic
properties and play an important role in the destruction of parasites that are too large to be phagocytosed.
Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma.
NK cells (also known as large granular lymphocytes [LGLs]) play a major role in the rejection of tumours
and the destruction of cells infected by viruses. Destruction of infected cells is achieved through the
release of perforins and granzymes from NK-cell granules which induce apoptosis (programmed cell
death) [4]. The main characteristics and functions of the cells involved in the innate immune response are
summarized in Figure 1.

Innate immunity can be viewed as comprising four types of defensive barriers: anatomic (skin and
mucous membrane), physiologic (temperature, low pH and chemical mediators), endocytic and
phagocytic, and inflammatory. Table 1summarizes the non-specific host-defense mechanisms for each of
these barriers.

Table 1
Summary of non-specific host-defense mechanisms for barriers of innate immunity [1].

Barrier Mechanism

Anatomic

• Mechanical barrier retards entry of microbes

Skin
• Acidic environment (pH 3-5) retards growth of microbes

• Normal flora compete with microbes for attachment sites

Mucous
• Mucous entraps foreign microbes
membrane
• Cilia propel microbes out of body

Physiologic

Temperature • Body temperature/fever response inhibits growth of some pathogens

Low pH • Acidic pH of stomach kills most undigested microbes

• Lysozyme cleaves bacterial cell wall

Chemical
• Interferon induces antiviral defenses in uninfected cells
mediators
• Complement lyses microbes or facilitates phagocytosis

Phagocytic/endocytic barriers

• Various cells internalize (endocytosis) and break down foreign macromolecules

  • Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize
(phagocytose), kill and digest whole organisms

Inflammatory barriers
 Barrier Mechanism

• Tissue damage and infection induce leakage of vascular fluid containing serum
  protein with antibacterial activity, leading to influx of phagocytic cells into the
affected area

Adaptive immunity
Adaptive immunity develops when innate immunity is ineffective in eliminating infectious agents and the
infection is established. The primary functions of the adaptive immune response are the recognition of
specific “non-self” antigens in the presence of “self” antigens; the generation of pathogen-specific
immunologic effector pathways that eliminate specific pathogens or pathogen-infected cells; and the
development of an immunologic memory that can quickly eliminate a specific pathogen should
subsequent infections occur [2]. The cells of the adaptive immune system include: T cells, which are
activated through the action of antigen presenting cells (APCs), and B cells.

T cells and APCs

T cells derive from hematopoietic stem cells in bone marrow and, following migration, mature in the
thymus. These cells express a unique antigen-binding receptor on their membrane, known as the T-cell
receptor (TCR), and as previously mentioned, require the action of APCs (usually dendritic cells, but also
macrophages, B cells, fibroblasts and epithelial cells) to recognize a specific antigen.

The surfaces of APCs express cell-surface proteins known as the major histocompatibility complex
(MHC). MHC are classified as either class I (also termed human leukocyte antigen [HLA] A, B and C)
which are found on all nucleated cells, or class II (also termed HLA, DP, DQ and DR) which are found on
only certain cells of the immune system, including macrophages, dendritic cells and B cells. Class I MHC
molecules present endogenous (intracellular) peptides while class II molecules present exogenous
(extracellular) peptides. The MHC protein displays fragments of antigens (peptides) when a cell is
infected with a pathogen or has phagocytosed foreign proteins [2, 3].

T cells are activated when they encounter an APC that has digested an antigen and is displaying antigen
fragments bound to its MHC molecules. The MHC-antigen complex activates the TCR and the T cell
secretes cytokines which further control the immune response. This antigen presentation process
stimulates T cells to differentiate into either cytotoxic T cells (CD8+ cells) or T-helper (Th) cells (CD4+
cells) (see Figure 2). Cytotoxic T cells are primarily involved in the destruction of cells infected by
foreign agents. They are activated by the interaction of their TCR with peptide-bound MHC class I
molecules. Clonal expansion of cytotoxic T cells produces effector cells which release perforin and
granzyme (proteins that causes lysis of target cells) and granulysin (a substance that induces apoptosis of
target cells). Upon resolution of the infection, most effector cells die and are cleared by phagocytes.
However, a few of these cells are retained as memory cells that can quickly differentiate into effector
cells upon subsequent encounters with the same antigen [2, 3].
Figure 2. Adaptive immunity: T-cell and B-cell activation and function. APC: antigen-presenting cell;
TCR: T-cell receptor; MHC: major histocompatibility complex Figure adapted from images available at:
http://en.wikipedia.org/wiki/Image:B_cell_activation.png and
http://commons.wikimedia.org/wiki/Image:Antigen_presentation.svg

T helper (Th) cells play an important role in establishing and maximizing the immune response. These
cells have no cytotoxic or phagocytic activity, and cannot kill infected cells or clear pathogens. However,
they "mediate" the immune response by directing other cells to perform these tasks. Th cells are activated
through TCR recognition of antigen bound to class II MHC molecules. Once activated, Th cells release
cytokines that influence the activity of many cell types, including the APCs that activate them.

Two types of Th cell responses can be induced by an APC: Th1 or Th2. The Th1 response is
characterized by the production of interferon-gamma (IFN-γ) which activates the bactericidal activities of
macrophages, and other cytokines that induce B cells to make opsonizing (coating) and neutralizing
antibodies. The Th2 response is characterized by the release of cytokines (interleukin-4, 5 and 13) which
are involved in the activation and/or recruitment of immunoglobulin E (IgE) antibody-producing B cells,
mast cells and eosinophils. As mentioned earlier, mast cells and eosinophils are instrumental in the
initiation of acute inflammatory responses, such as those seen in allergy and asthma. IgE antibodies are
also associated with allergic reactions (see Table 2). Therefore, an imbalance of Th2 cytokine production
is associated with the development of atopic (allergic) conditions. Like cytotoxic T cells, most Th cells
will die upon resolution of infection, with a few remaining as Th memory cells [2, 3].

A third type of T cell, known as the regulatory T cell (T reg), also plays a role in the immune response. T
reg cells limit and suppress the immune system and, thereby, may function to control aberrant immune
responses to self-antigens and the development of autoimmune disease.

Table 2
Major functions of human Ig antibodies [5].

Ig
Function
antibody

First immunoglobulin (Ig) expressed during B cell development (primary response; early
antibody)
IgM
• Opsonizing (coating) antigen for destruction
• Complement fixation

Main Ig during secondary immune response

• Only antibody capable of crossing the placental barrier
IgG • Neutralization of toxins and viruses
• Opsonizing (coating) antigen for destruction
• Complement fixation

IgD Function unclear; appears to be involved in homeostasis

Mucosal response; protects mucosal surfaces from toxins, viruses and bacteria through
IgA
either direct neutralization or prevention of binding to mucosal surface

Associated with hypersensitivity and allergic reactions

IgE
• Plays a role in immune response to parasites

B cells
B cells arise from hematopoietic stem cells in the bone marrow and, following maturation, leave the
marrow expressing a unique antigen-binding receptor on their membrane. Unlike T cells, B cells can
recognize free antigen directly, without the need for APCs. The principal function of B cells is the
production of antibodies against foreign antigens [2, 3].

When activated by foreign antigens, B cells undergo proliferation and differentiate into antibody-
secreting plasma cells or memory B cells (see Figure 2). Memory B cells are “long-lived” survivors of
past infection and continue to express antigen-binding receptors. These cells can be called upon to
respond quickly and eliminate an antigen upon re-exposure. Plasma cells, on the other hand, do not
express antigen-binding receptors. These are short-lived cells that undergo apoptosis when the inciting
agent that induced the immune response is eliminated.
Given their function in antibody production, B cells play a major role in the humoral or antibody-
mediated immune response (as opposed to the cell-mediated immune response, which is governed
primarily by T cells) [2, 3].

Antibody-mediated vs. cell-mediated immunity

Antibody-mediated immunity is the branch of the acquired immune system that is mediated by B-cell
antibody production. The antibody-production pathway begins when the B cell’s antigen-binding receptor
recognizes and binds to antigen in its native form. This, in turn, attracts the assistance of Th cells which
secrete cytokines that help the B cell multiply and mature into antibody-secreting plasma cells. The
secreted antibodies bind to antigens on the surface of pathogens, flagging them for destruction through
pathogen and toxin neutralization, classical complement activation, opsonin promotion of phagocytosis
and pathogen elimination. Upon elimination of the pathogen, the antigen-antibody complexes are cleared
by the complement cascade (see Figure 2) [2].

Five types of antibodies are produced by B cells: immunoglobulin A (IgA), IgD, IgE, IgG and IgM. Each
of these antibodies has differing biological functions and recognize and neutralize specific pathogens.
Table 2 summarizes the various functions of the five Ig antibodies [5].
Antibodies play an important role in containing virus proliferation during the acute phase of infection.
However, they are not generally capable of eliminating a virus once infection has occurred. Once an
infection is established, cell-mediated immune mechanisms are most important in host defense.

Cell-mediated immunity does not involve antibodies, but rather protects an organism through [2]:
 the activation of antigen-specific cytotoxic T cells that induce apoptosis of cells
displaying epitopes (localized region on the surface of an antigen that is capable of
eliciting an immune response) of foreign antigen on their surface, such as virus-infected
cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
 the activation of macrophages and NK cells, enabling them to destroy intracellular
pathogens; and
 the stimulation of cytokine production that further mediates the immune response.

Cell-mediated immunity is directed primarily at microbes that survive in phagocytes as well as those that
infect non-phagocytic cells. This type of immunity is most effective in eliminating virus-infected cells,
but can also participate in defending against fungi, protozoa, cancers, and intracellular bacteria. Cell-
mediated immunity also plays a major role in transplant rejection.

Passive vs. active immunization

Acquired immunity is attained through either passive or active immunization. Passive immunization
refers to the transfer of active humoral immunity, in the form of “ready-made” antibodies, from one
individual to another. It can occur naturally by transplacental transfer of maternal antibodies to the
developing fetus, or it can be induced artificially by injecting a recipient with exogenous antibodies
targeted to a specific pathogen or toxin. The latter is used when there is a high risk of infection and
insufficient time for the body to develop its own immune response, or to reduce the symptoms of chronic
or immunosuppressive diseases.
Active immunization refers to the production of antibodies against a specific agent after exposure to the
antigen. It can be acquired through either natural infection with a microbe or through administration of a
vaccine that can consist of attenuated (weakened) pathogens or inactivated organisms,

Immunopathology
As mentioned earlier, defects or malfunctions in either the innate or adaptive immune response can
provoke illness or disease. Such disorders are generally caused by an overactive immune response
(known as hypersensitivity reactions), an inappropriate reaction to self (known as autoimmunity) or
ineffective immune responses (known as immunodeficiency).

Hypersensitivity reactions
Hypersensitivity reactions refer to undesirable responses produced by the normal immune system. There
are four types of hypersensitivity reactions [6, 7]:
 Type I: immediate hypersensitivity
 Type II: cytotoxic or antibody-dependent hypersensitivity
 Type III: immune complex disease
 Type IV: delayed-type hypersensitivity

Type I hypersensitivity is the most common type of hypersensitivity reaction. It is an allergic reaction
provoked by re-exposure to a specific type of antigen, referred to as an allergen. Unlike the normal
immune response, the type I hypersensitivity response is characterized by the secretion of IgE by plasma
cells. IgE antibodies bind to receptors on the surface of tissue mast cells and blood basophils, causing
them to be “sensitized”. Later exposure to the same allergen, cross-links the bound IgE on sensitized cells
resulting in degranulation and the secretion of active mediators such as histamine, leukotriene, and
prostaglandin that cause vasodilation and smooth-muscle contraction of the surrounding tissue. Common
environmental allergens inducing IgE-mediated allergies include cat-, dog- and horse epithelium, pollen,
house dust mites and molds. Food allergens are also a common cause of type I hypersensitivity reactions,
however, these types of reactions are more frequently seen in children than adults. Treatment of type I
reactions generally involves trigger avoidance, and in the case of inhaled allergens, pharmacological
intervention with bronchodilators, antihistamines and anti-inflammatory agents. More severe cases may
be treated with immunotherapy.

Type II hypersensitivity reactions are rare and take anywhere from 2 to 24 hours to develop. These
types of reactions occur when IgG and IgM antibodies bind to the patient’s own cell-surface molecules,
forming complexes that activate the complement system. This, in turn, leads to opsonization, red blood
cell agglutination (process of agglutinating or “clumping together”), cell lysis and death. Some examples
of type II hypersensitivity reactions include: erythroblastosis fetalis, Goodpasture’s syndrome, and
autoimmune anemias.

Type III hypersensitivity reactions occur when IgG and IgM antibodies bind to soluble proteins (rather
than cell surface molecules as in type II hypersensitivity reactions) forming immune complexes that can
deposit in tissues, leading to complement activation, inflammation, neutrophil influx and mast cell
degranulation. This type of reaction can take hours, days, or even weeks to develop and treatment
generally involves anti-inflammatory agents and corticosteroids. Examples of type III hypersensitivity
reactions include systemic lupus erythematosus (SLE), serum sickness and reactive arthritis.
Unlike the other types of hypersensitivity reactions, type IV reactions are cell-mediated and antibody-
independent. They are the second most common type of hypersensitivity reaction and usually take 2 or
more days to develop. These types of reactions are caused by the overstimulation of T cells and
monocytes/macrophages which leads to the release of cytokines that cause inflammation, cell death and
tissue damage. In general, these reactions are easily resolvable through trigger avoidance and the use of
topical corticosteroids.

A brief summary of the four types of hypersensitivity reactions is provided in Table 3.

Table 3. Types of hypersensitivity reactions [6, 7]

Typ
Alternate name Examples Mediators
e

Atopy
• — Anaphylaxis
• — Asthma
I Allergy (immediate) IgE
• — Allergic rhinitis
• — Angioedema
• — Food allergy

Erythroblastosis fetalis
• Goodpasture’s syndrome
II Cytotoxic, antibody-dependent IgG, IgM
• Autoimmune anemias,
thrombocytopenias

Systemic lupus erythematosus Aggregation of

• Serum sickness antigens IgG, IgM
III Immune complex disease
• Reactive arthritis Complement
• Arthrus reaction proteins

Contact dermatitis
Delayed-type hypersensitivity, cell- T cells, monocytes,
IV • Tuberculosis
mediated, antibody-independent macrophages
• Chronic transplant rejection

Autoimmunity
Autoimmunity involves the loss of normal immune homeostasis such that the organism produces an
abnormal response to its own tissue. The hallmark of autoimmunity is the presence of self-reactive T
cells, auto-antibodies, and inflammation. Prominent examples of autoimmune diseases include: Celiac
disease, type 1 diabetes mellitus, Addison’s disease and Graves’ disease [8].

Immunodeficiency
Immunodeficiency refers to a state in which the immune system's ability to fight infectious disease is
compromised or entirely absent. Immunodeficiency disorders may result from a primary congenital defect
(primary immunodeficiency) or may be acquired from a secondary cause (secondary immunodeficiency),
such as viral or bacterial infections, malnutrition or treatment with drugs that induce immunosuppression.
Certain diseases can also directly or indirectly impair the immune system such as leukemia and multiple
myeloma. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS),
caused by the human immunodeficiency virus (HIV). HIV directly infects Th cells and also impairs other
immune system responses indirectly [9, 10].

Conclusion
Innate immunity is the first immunological, non-specific mechanism for fighting against infections. This
immune response is rapid, occurring minutes or hours after aggression and is mediated by numerous cells
including phagocytes, T cells, mast cells, basophils and eosinophils, as well as the complement system.
Adaptive immunity develops in conjunction with innate immunity to eliminate infectious agents; it relies
on the tightly regulated interplay between T cells, APCs and B cells. A critical feature of adaptive
immunity is the development of immunologic memory or the ability of the system to learn or record its
experiences with various pathogens, leading to effective and rapid immune responses upon subsequent
exposure to the same or similar pathogens. A brief overview of the defining features of innate and
adaptive immunity are presented in Table 4.

Table 4. Overview of the defining features of innate and adaptive immunity [1].
  Innate immune system Adaptive immune system

Hematopoietic cells:
• macrophages
• dendritic cells
• mast cells
• neutrophils
Hematopoietic cells:
• basophils
Cells • T cells
• eosinophils
• B cells
• NK cells
• T cells
• non-hematopoietic cells
• epithelial cells (skin, airways,
gastrointestinal tract)

cytokines
antibodies (Ig)
Molecules • complement
• cytokines
• proteins and glycoprotein
   Innate immune system Adaptive immune system

Response time immediate delayed by hours to days

Immunologic none: responses are the same with each responsiveness enhanced by
memory exposure repeated antigen exposure

There is a great deal of synergy between the adaptive immune system and its innate counterpart, and
defects in either system can lead to immunopathological disorders, including autoimmune diseases,
immunodeficiencies and hypersensitivity reactions. The remainder of this supplement will focus on the
appropriate diagnosis, treatment and management of some of these more prominent disorders, particularly
those associated with hypersensitivity reactions.

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