Allergy and Hypersensitivity
W Xing and VK Vanguri, University of Massachusetts Medical School, Worcester, MA, USA
ã 2014 Elsevier Inc. All rights reserved.
Glossary
Allergy A rapid immune response mediated by preformed
antigen-specific IgE and subsequent mast cell degranulation.
Anaphylaxis A profound form of allergy with life-
threatening respiratory and circulatory effects caused by
systemic release of allergic mediators in response to antigen
to which the immune system has been previously sensitized.
Antibody Secreted forms of the B-cell receptor that
recognize antigen; also known as immunoglobulin.
Antigen A molecule that can be recognized by antibodies
and antibody-like molecules to elicit an immune response.
Cell-mediated hypersensitivity A pathway of tissue damage
mediated by helper and effector T cells after T-cell activation
by antigen-presenting cells.
Class switching The developmental mechanism that
produces different immunoglobulins of the same specificity
but with distinct heavy chain-dependent effector
functionality.
Cognate The specific, correlative binding partner in
interactions between antigen and antibody or between
peptide–MHC and the T-cell receptor.
Abbreviations
IL Interleukin
MHC Major histocompatibility complex
While the immune system normally protects the body against
pathogens and foreign substances, the same mechanisms of
host defense can cause hyperreactivity of the immune response
that in turn can lead to damage of host tissues. The mecha-
nisms that lead to this collateral damage are termed ‘hypersen-
sitivity,’ and they engage components of both the adaptive
and innate immune systems in the response to antigens.
The three fundamental modes of hypersensitivity include (1)
allergy, (2) B-cell- or antibody-mediated hypersensitivity, and
(3) T-cell-mediated hypersensitivity. Autoimmune diseases
such as asthma, systemic lupus erythematosus, type 1 diabetes,
and sarcoidosis, each employ one or more of these mecha-
nisms concurrently during states of active pathology.
While the initial triggers in some hypersensitivity reactions
can be discernible antigens such as pollen, a bee sting, or a
drug, in most cases, the antigenic trigger is not often known.
The trigger may also have been transient and short-lived yet
still initiate a cascade of continued immunity and host dam-
age. Combating pathological tissue damage from hypersensi-
tivity, therefore, is rarely just the act of removing a known
stimulus but rather involves controlling the cells and cytokines
36 Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
Delayed-type hypersensitivity Also known as cell-mediated
hypersensitivity.
Epitope The structural portion of a molecule recognized by
an antibody.
Granuloma An aggregate of activated macrophages and
associated T cells that forms as a consequence of cell-
mediated hypersensitivity for clearance or neutralization of
undigestible foreign material or pathogens that evade
intracellular killing.
Histamine A molecule released by degranulated mast cells
and other allergic responders that mediates important local
effects on tissue that form the key clinical features of the
allergic response.
Hypersensitivity An exaggerated immune response that
produces injury to host tissue.
Immediate hypersensitivity Also known as allergy.
Membrane attack complex A molecular assembly of
complement components C5b–C9 that induces perforations
in cell membranes of antibody-coated pathogens or cells.
Opsonization The phenomenon of antibody binding to a
target cell or pathogen that induces complement-assisted
clearance of the coated target by phagocytes.
Th Helper T cell
TSH Thyroid-stimulating hormone
that comprise the complex web of immune regulation, mem-
ory, and checkpoints of tolerance that are set in motion by
antigen exposure.
Allergy
The most rapid of the fundamental hypersensitivity responses
is allergy, also known as immediate hypersensitivity. After an
initial period of sensitization by a culprit antigen, IgE mole-
cules able to recognize this antigen increase in density in
vulnerable tissues depending on the expected route of antigen
entry, such as the lung and airway for respiratory antigens
(such as in asthma), intestinal mucosa for ingested antigens,
or dermis for contact antigens. Upon rechallenge with the same
antigen, the preformed IgE molecules bind the antigen and are
recognized by tissue-resident mast cells through their surface
IgE receptors (FceRI). The cross-linking of IgE and engagement
of FceRI lead to degranulation of the mast cell, often within
minutes of antigen entry in sensitized individuals due to the
http://dx.doi.org/10.1016/B978-0-12-386456-7.01108-4

abundance of preformed antigen-specific antibody and the
high affinity of the receptor/immunoglobulin interaction.
At this point, mast cells (and basophils, which share
several of these functions) release several substances from
intracellular granules that act locally to produce the immediate
hypersensitivity reaction. Most notably is histamine, a power-
ful amine that elicits many of the local tissue responses associ-
ated with immediate hypersensitivity, such as redness (via a
vasodilatory effect), swelling (via an increase in vascular per-
meability), bronchoconstriction in asthma (via smooth muscle
contraction), and pain or itching (via a neuronal effect). Sev-
eral other mediators are also released depending on the tissue
involved and the resident mast cell population, including ara-
chidonic acid regulators and cytokines that elicit T-cell effector
and memory responses. If released systemically in large enough
quantities, these same mediators can cause the potentially fatal
form of immediate hypersensitivity known as anaphylaxis.
The T-cell response involved in allergy is skewed to the Th2
axis, and it plays key roles in the initial sensitization phase,
rechallenge, and a persistent state of heightened responsive-
ness in chronic allergic states. At the outset, the antigen is
processed and presented by antigen-presenting cells to naive
CD4 T cells via major histocompatibility complex (MHC)
class II. These T cells differentiate into IL-4-, IL-5-, and IL-13-
producing Th2 cells that coordinate class switching to IgE upon
engagement with cognate B cells. The local antigen-specific IgE
milieu is thus created, primed, and ready for rechallenge. With
persistent antigen exposure, the Th2 microenvironment can
sustain chronic inflammation and reparative changes in the
affected tissue, actively promoting hyperresponsiveness with
even greater densities of antigen-specific IgE and other allergic
responders such as mast cells, basophils, and eosinophils.
Antibody-Mediated Hypersensitivity
The B-cell arm of the adaptive immune system participates in
hypersensitivity reactions in several ways, mainly through anti-
body production. While immediate hypersensitivity involves
IgE and mast cell degranulation, classical antibody-mediated
hypersensitivity involves the binding and cross-linking of
antigen-specific antibodies to targets, in many cases followed
by complement fixation and either by destruction of the C5b–
C9 membrane attack complex or by deposition and aggrega-
tion of immune complexes and recruitment of phagocytes.
Antibodies generated in an immune response directed against
a pathogen can also cross-react with epitopes on self-
molecules, aberrantly labeling host tissues themselves as
targets for antibody-dependent clearance mechanisms. It is
important to note that although the dominant, reductionist
principle in this group of hypersensitivity reactions involves
antibody, experimental models and studies of human disease
in many cases highlight defects of T cells or antigen-presenting
cells at nodes of antigen presentation, costimulation, class
switching in the lymphoid follicle, or other developmental
mechanisms of tolerance that ultimately lead to an undesired
humoral response.
Antibody can bind to fixed antigens on cells and tissues,
leading to host damage. Recognition of fixed antigen plays a
role in diseases such as Goodpasture syndrome, in which an
Adaptive Immunity | Allergy and Hypersensitivity 37
autoantibody is directed against an epitope of type IV collagen,
specifically in the noncollagenous region of the a3 collagen
subunit, leading to lung and/or kidney damage due to the
tissue distribution of type IV collagen. The autoantibody elicits
complement binding and induces acute inflammation locally,
leading to basement membrane breaks and organ-threatening
hematuria and glomerulonephritis or even life-threatening
alveolar hemorrhage. Experimental models in which such anti-
bodies are transferred to a naive organism can generate passive
immunity in this manner, underscoring the pathogenicity of
the antibody and to the clinical use of plasmapheresis in
managing disease manifestations by reducing the circulating
antibody load.
Antibody–antigen immune complexes can also form in
circulation and precipitate out of serum or deposit in specific
vascular beds and tissues as a result of solubility consider-
ations, pressure and flow in the microenvironment, or size
and charge characteristics of the immune complex. In diseases
such as systemic lupus erythematosus, these immune deposits
become hot spots of aggregated Fc receptors and complement,
inducing phagocyte recruitment. In many ways, this response
is akin to that used in opsonization of pathogens by antibody
and subsequent clearance of the foreign invaders. The non-
antigen-specific phagocytic response of the innate immune
system responds to antibody and complement aggregates
with receptor-mediated internalization into the phagolyso-
some. Inadvertently, elaborated lysosomal enzymes during
this process of internalization appear to cause lytic damage to
nearby cells and matrix. Clearance of the seemingly opsonized
particles may be physiologically desired, but in the case of
hypersensitivity, undesired tissue damage occurs due to the
local effects of inflammation and enzymatic digestion of the
proximal cells and tissues through the elaborated proteases
from the lysosome.
Even without the complement cascade, antibody binding to
its epitope can also play a stimulatory or inhibitory role, and
most consider this phenomenon as a form of antibody-
mediated hypersensitivity. Graves’ disease is a thyroid disease
in which autoantibodies bind to the receptor for thyroid-
stimulating hormone (TSH) on the surface of thyroid follicular
epithelium. The autoantibodies can be stimulating to the
receptor leading to hyperthyroidism or can be inhibitory
through blockade and competition with TSH, leading to
hypothyroidism.
Cell-Mediated Hypersensitivity
The T-cell arm of the adaptive immune system is also involved
in many ways in hypersensitivity responses. In addition to the
roles of T cells described in the text earlier in immediate hyper-
sensitivity, there is accruing experimental evidence that T cells
are often a necessary component of generation or propagation
of antibody-dependent or antibody-independent autoimmune
responses, as adoptive transfer of sensitized T cells from organ-
isms with experimental disease can elicit pathogenic responses
in naive recipients. In contrast to immediate hypersensitivity,
however, T-cell engagement in an immune response is most
productive when a T-cell clone with defined specificity engages
its cognate peptide–MHC on an antigen-presenting cell,
38 Adaptive Immunity | Allergy and Hypersensitivity
usually in a secondary lymphoid organ. A coordinated T-cell
response, therefore, takes 7–10 days with a naive repertoire,
leading to the characterization of hypersensitivity reactions
with prominent cell components as ‘delayed-type’ hypersensi-
tivity. If a significant memory population exists, T-cell-
mediated hypersensitivity can be elicited more briskly, even
within 1–3 days of rechallenge.
The archetype of delayed-type hypersensitivity is granulo-
matous inflammation, in which CD4þ T-cell-dependent
aggregates of activated macrophages and associated lympho-
cytes develop in tissues. Granulomatous inflammation is
exemplified in the host response to Mycobacterium tuberculosis
and other organisms that resist intracellular killing and foreign
material that is essentially enzymatically undigestible to mono-
nuclear phagocytes. Sarcoidosis shows chronic granulomatous
inflammation without a clear antigenic trigger or pathogen.
Under polarized Th1 conditions, the T cells proliferate, as do
the macrophages, which are also primed for intracellular
destruction despite the resistance of the surviving particle.
The granuloma helps to wall off the tissue affected to prevent
dissemination of the entrapped but still viable microbe, often
resulting in a significant amount of collateral tissue
destruction.
With recent advances in our knowledge of the mechanisms
of T-cell differentiation and involvement in so many facets of
an adaptive immune response, it is apparent that there are
many more avenues for T-cell-mediated host damage. T cells
with Th2 polarization play roles in class switching and perpet-
uation of inflammation in allergic reactions. Tfh cells are
involved in directing the actions of B cells and antibody
production at play in antibody-mediated hypersensitivity reac-
tions as well. CD4 þ T cells can initiate host damage through
direction of inflammation in Th1 or Th17 responses, and
indeed, autoimmune diseases such as rheumatoid arthritis
and type 1 diabetes appear due to a loss of T-cell tolerance
with the engagement of effector cells such as cytotoxic CD8 þ T
cells and neutrophils through IFNg and IL-17-rich cytokine
milieus in precipitating tissue injury. Interestingly, the second-
ary lymphoid organs and affected peripheral tissues in murine
models of these autoimmune diseases can contain several
T-cell subsets indicating concomitant patterns of T-cell differ-
entiation, suggesting that host damage can occur through the
engagement of multiple simultaneous mechanisms of
hypersensitivity.
Further Reading
Barnes, P.J., 2011. Pathophysiology of allergic inflammation. Immunol. Rev. 242,
31–50.
Galli, S.J., Tsai, M., Piliponsky, A.M., 2008. The development of allergic inflammation.
Nature 454, 445–454.
King, C., Tangye, S.G., Mackay, C.R., 2008. T follicular helper (TFH) cells in normal and
dysregulated immune responses. Annu. Rev. Immunol. 26, 741–766.
Ramakrishnan, L., 2012. Revisiting the role of the granuloma in tuberculosis. Nat. Rev.
Immunol. 12, 352–366.
Tsai, S., Santamaria, P., 2013. MHC class II polymorphisms, autoreactive T-cells, and
autoimmunity. Front. Immunol. 4, 321.
Weinstein, J.S., Hernandez, S.G., Craft, J., 2012. T cells that promote B-cell maturation
in systemic autoimmunity. Immunol. Rev. 247, 160–171.
Zhu, J., Yamane, H., Paul, W.E., 2010. Differentiation of effector CD4 T cell populations
(*). Annu. Rev. Immunol. 28, 445–489.