Journal of Allergy and Clinical Immunology

Volume 125, Issue 2, Supplement 2, February 2010, Pages S73S80

2010 Primer on Allergic and Immunologic Diseases

IgE, mast cells, basophils, and eosinophils
Kelly D. Stone, MD, PhD, Calman Prussin, MD, Dean D. Metcalfe,
MD
,

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Md
IgE, mast cells, basophils, and eosinophils
Journal of Allergy and Clinical Immunology, Volume 125, Issue 2, Supplement 2,
February 2010, Page S350


IgE, mast cells, basophils, and eosinophils are essential components of
allergic inflammation. Antigen-specific IgE production, with subsequent
fixation of IgE to FcRI receptors on mast cells and basophils, is central to
the initiation and propagation of immediate hypersensitivity reactions. Mast
cells, basophils, and eosinophils are central effector cells in allergic
inflammation, as well as in innate and adaptive immunity. This review
highlights what is known about these components and their roles in
disease pathogenesis.






Mechanisms of IgE Inflammation.
Rosenwasser LJ.
Source
Allergy-Immunology Division, Children's Mercy Hospital, University of Missouri-Kansas
City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA.
Abstract
The prevalence of diseases such as allergic asthma and rhinitis continues
to increase in the United States, affecting millions of people. It is well-
established that allergy contributes to the pathogenesis of most asthma,
especially in children and young adults. Despite current therapy (eg,
inhaled corticosteroids, anti-leukotrienes, and bronchodilators), patients
with moderate to severe asthma remain symptomatic and experience
frequent exacerbations of disease requiring oral corticosteroids,
emergency department treatments, and hospitalizations. Allergic diseases
are traditionally referred to as immediate or type 1 hypersensitivity
reactions, with IgE as a critical factor. IgE is involved in allergic
inflammation, especially in early-phase response, but it may also be
involved in the late-phase allergic response. A direct correlation between
serum IgE levels and asthma exists. As logarithm IgE values increase,
asthma prevalence increases linearly, even in patients who are
categorized as having nonallergic asthma. In addition, there is a
significant, although low association in allergic rhinitis with IgE levels and
positive skin test reactivity to pollens. Recent advances in our
understanding of the role of IgE in allergic inflammation have led to the
development of a monoclonal antibody to IgE that reduces IgE levels,
thereby reducing allergic inflammation. This review aims to provide an
overview of the basic science of the IgE molecule and the clinical efficacy
of anti-IgE therapy in allergic and asthmatic diseases.



IgE An overlooked regulator of
allergic disease
Daniel H. Conrad PhD, Jill W. Ford PhD, Jamie L. Sturgill BS, David
R. Gibb BS
Abstract
Given the importance of immunoglobulin (Ig) E in mediating type I
hypersensitivity, inhibiting IgE production would be a general way of
controlling allergic disease. The low-affinity IgE receptor (Fc!RII or CD23)
has long been proposed to be a natural regulator of IgE synthesis. In vivo
research supporting this concept includes the observation that mice
lacking CD23 have increased IgE production whereas mice
overexpressing CD23 show strongly suppressed IgE responses. In
addition, the finding that mice injected with monoclonal antibody directed
against the coiled-coil stalk of CD23 have enhanced soluble CD23 release
and increased IgE production demonstrates that full-length, trimeric CD23
is responsible for initiating an IgE inhibitory signal. The recent
identification of ADAM10 (a disintegrin and metalloprotease) as the CD23
metalloprotease provides an alternative approach for designing therapies
to combat allergic disease. Current data suggest that stabilizing cell-
surface CD23 would be a natural means to decrease IgE synthesis and
thus control type I hypersensitivity.






Anti-IgE monoclonal antibody (omalizumab) in the
treatment of atopic asthma and allergic respiratory
diseases.
D'Amato G, Liccardi G, Noschese P, Salzillo A, D'Amato M, Cazzola M.
Source
Division of Respiratory and Allergic Diseases, Department of Chest Diseases, High
Speciality Hospital A Cardarelli, Naples, Italy.
Abstract
Since the discovery of immunoglobulin E (IgE) antibodies thirty-six years
ago, our understanding of the mechanisms of allergy has improved to such
an extent that we can now better differentiate allergy from non-allergic
hypersensitivity, and allergic/atopic from intrinsic/non-atopic bronchial
asthma. IgE antibodies are crucial immune mediators of airway
inflammation in allergic atopic asthma and IgE-mediated hypersensitivity
reactions are the likely mechanisms of allergen-induced airway
obstruction. In addition, IgE may cause chronic airway inflammation in
asthma through effector cells activated via high-affinity (Fcepsilon RI) or
low-affinity (Fcepsilon RII) IgE receptors. Therapeutic anti-IgE antibodies
able to reduce free IgE levels and to block the binding of IgE to Fcepsilon
RI without cross-linking IgE and triggering degranulation of IgE-sensitised
cells have been developed. This non-anaphylactogenic anti-IgE
monoclonal antibody (rhuMAb-E25; omalizumab) binds IgE at the same
site as these antibodies bind Fcepsilon RI and Fcepsilon RII. As a
consequence, omalizumab inhibits IgE effector functions by blocking IgE
binding to high-affinity receptors on IgE effector cells and does not cause
mast cell or basophil activation because it cannot bind to IgE on cell
surfaces where the Fcepsilon R1 receptor already masks the anti-IgE
epitope. Studies in patients with atopic asthma demonstrated that
omalizumab decreases serum IgE levels and allergen-induced
bronchoconstriction during both the early and late-phase responses to
inhaled allergen. In several clinical controlled trials omalizumab resulted to
be able to reduce asthma-related symptoms, to decrease corticosteroid
use and to improve quality of life of asthmatic patients. The anti-IgE
approach to asthma treatment has several advantages, including
concomitant treatment of other IgE-mediated diseases (allergic rhinitis,
allergic conjunctivitis, atopic dermatitis and food allergies), a favourable
side-effect profile and a twice-monthly dosing frequency.




Categories of inflammation
mediated by the immune
systemThe immune processes are probably ongoing and, in
most cases, lead to the elimination of antigens without producing
clinically detectable inflammation. The development of clinically
apparent inflammation indicates that the immune system has
encountered either an unusually large amount of antigen, antigen in
an unusual location, or antigen that is dificult to digest. In some
diseases, such as rhematoid arthritis, the iniciating agent is
unknown or may be normal host tissue components. In others (e.g.
systemic lupus erythematosus), inherent or acquired
immunoregulatory abnormalities may contribute to the sustained
nature of the inflammatory process.Coombs and Gell divided
inflammatory responses mediated by the immune system into four
categories, called I, II, III, and IV, which represent four distinct
immune mechanisms that result in tissue injury. These same four
processes represent mechanisms of immune protection from
infectious agents:
I. Immediate hypersensitivity (allergic, or reaginic acute
inflammation).
II. Cytotoxic (inflammation mediated by cytotoxic antibodies).
III. Immune complex (inflammation mediated by immune
complex).

IV. Delayed hypersensitivity (chronic inflammation mediated
by lymphocytes and macrophages).


Allergic (reaginic) acute inflammation
Type I hypersensitivity is characterized by an allergic reaction that
occurs immediately following contact with antigen, which is
referred to as the allergen. The term allergy means ''changed
reactivity'' of the host when meeting an ''agent'' on a second or
subsequent occasion. In some individuals certain allergens have a
propensity to stimulate production of IgE antibodies. IgE
antibodies bind nonspecifically, via their high affinity Fc receptors,
to mast cells and basophils. Subsequent attachment of antigen to
the Fab portion of cell-bound IgE antibodies results in release of
contents of cytoplasmic granules from mast cells and basophils
(e.g. histamine), as well as in synthesis and secretion of
biologically active products of arachidonic acid (e.g. leukotrienes).
Mast cell products increase vascular permeability and constrict
bronchial smooth muscle. A wheal and flare reaction occurs within
seconds to minutes. Neutrophils and eosinophils characteristically
predominate and mononuclear cells can also be seen.
Reaginic reactions are responsible for such allergic phenomena as
urticaria, seasonal rhinitis, asthma, and in settings where large
amounts of antigens (allergens) enter the host circulation, systemic
anaphylaxis. These occur when an IgE response is directed against
innocuous enviromental antigens, such as pollen, house-dust mites
or animal dander. The resulting release of pharmacological
mediators by IgE-sensitized mast cell produces an acute
inflammatory reaction with symptoms such as asthma or rhinitis.
The importance of type I reactions in protection from infectious
organisms is uncertain, although the increased vascular
permeability mediated by these reactions probably facilitates the
capacity of antibody and inflammatory cells to arrive at the
infected site. In addition, homocytotropic IgE antibodies and cells
containing inflammatory mediators probably participate in the
defence against large, non-phagocytable organisms, most notably
the multicellular helminthic parasites.
There is an important question why one individual express atopic
diseases and another does not. At least two reasons exist --
environmental exposure and genetics. A third reason -- an external
event that alters IgE regulation -- may be important in certain
clinical situation but may represent a rare cause of atopic diseases.
The atopic diseases, allergic rhinitis, asthma, and atopic dermatitis
have a genetic component. Some or all of these clinical syndromes
can be present in a single member or in several member of the
same family. The natural history of atopic diseases is not known,
but it appears that atopic individuals appear to have a relatively
high frequency of food allergy before the age of two years; food
allergy then becomes rarer but the patients develop IgE antibodies
to inhalant allergens and manifest allergic rhinitis and/or asthma.
In general, atopy is a hereditary feature manifested by abnormal
immediated -- type hypersensitivity to a certain allergen or a group
of allergens.
Anaphylaxis denotes an acute systemic immediate reaction to
allergen, typically mediated by IgE antibodies. The mildest form of
anaphylaxis, involving only the skin, is termed urticaria or ''hives''.
More severe reactions involve the mucous membranes and the
gastrointestinal, pulmonary, and cardiovascular organs.
Anaphylaxis may be life-threatening. The manifestations range
from urticaria to angioedema (swelling of mucous membranes, for
example, of the lips, tongue, palate, and larynx), nausea and
vomiting (edema and smooth muscle contraction of gastrointestinal
tract), asthma (bronchial smooth muscle contraction), and
hypotension (increased vascular permeability resulting in a loss of
blood volume into tissue and thus a fall in blood pressure; reducing
contractility of the heart also contributes to hypotension). Life-
threatening reactions involve laryngeal edema, severe asthma, or
severe hypotension and circulatory collapse. Agents that induce
IgE-mediated anaphylaxis include penicillin, insect venoms, foods,
and occasionally immunotherapy (i.e. injection of allergen to
which a person is allergic, in order to treat allergic diseases).
Identical symptoms, which are not immune mediated, are
sometimes termed anaphylactoid. Anaphylactoid reactions may be
caused by radiocontrast dye (used for x-ray studies) and exercise.
Although antigen-IgE antibody interaction is the major cause of
anaphylaxis, other immune mechanisms may occasionally induce
the syndrome. Thus immune complexes may mediate anaphylaxis
in some patients who are IgA-deficient and receive infusions of
IgA, which interacts with preformed anti-IgA antibody.
Anaphylactoid reactions may also occur after repeated intravenous
administration of normal human immunoglobulin preparation that
contain more than 5% of IgG aggregates in agammaglobulinaemic
or hypogammaglobulinaemic patients. These aggregates activate
complement to produce C5a and C3a anaphylatoxins which
stimulate mediator release from basophils and perhaps some Type
II, or antibody-dependent cytotoxic hypersensitivity occurs
when antibody binds to either self antigen or foreign antigen on
cells, and leads to phagocytosis, killer cell activity or complement-
mediated lysis.
Both type II and type III hypersensitivity are caused by IgG and
IgM antibodies. The main distinction is that type II reactions
involved antibodies directed to antigens on the surface of specific
cells or tissues, whereas type III reactions involve antibodies
against widely distributed soluble antigens in the serum. Thus,
damage caused by type II reactions is localized to a particular
tissue or cell type, whereas damage caused by type III reactions
affects those organs where antigen-antibody complexes are
deposited.
These hypersensitivity reactions are related to normal immune
responses seen against microorganisms and larger multicellular
parasites. Indeed, in mounting a reaction to a pathogen,
exaggerated immune reactions may sometimes be as damaging to
the host as the effects of the pathogen itself. In such cases the
bordeline between a normal, useful immune response and
hypersensitivity is blurred. Hypersensitivity reactions may also
occur in many other conditions involving immune reactions,
particularly autoimmunity and transplantation.
In type II hypersensitivity, antibody directed against cell surface or
tissue antigens forms immune complex which interacts with
complement and a variety of effector cells to bring about damage
to the target cells. Antibodies can link the target cells to effectors
cells, such as macrophages, neutrophils, eosinophils and generally,
K cells, by means of Fc receptors on these effector cells. This is
so-called antibody-dependent cell-mediated cytotoxicity (ADCC).
Alternatively, the antibodies after binding to tissue antigens can
interact with complement by activating C1 of the classical
pathway. This results in the deposition of the C5b678(9)
n
membrane attack complex and following lysis of antibody-
sensitized cells.
Both the complement fragments and IgG can act as opsonins
bound to host tissues or to microorganisms, and phagocytes take
up the opsonized particles. By enhancing the lysosomal activity of
phagocytes, and potentiating their capacity to produce reactive
oxygen intermediates, the opsonins increase the phagocytes'
capacity to destroy pathogen, but also increase their ability to
produce immunopathological damage in hypersensitivity reactions.
For example, neutrophils from the synovial fluid of patients with
rhematoid arthritis produce more superoxide when stimulated than
neutrophils from the blood. This is thought to be related to their
activation, in the rheumatoid joint, by mediators which include
immune complexes and complement fragments.
The accumulation of inflammatory cells (neutrophils), with release
of neutrophil lysosomal enzymes and generation of toxic oxygen
intermediates, together with complement-mediated tissue lysis,
leads to destruction of tissues as in the glomerular and pulmonary
basement membrane damage in Goodpasture's syndrome or in the
autoimmune haemolytic anemia and immune-mediated
thrombocytopenia of systemic lupus erythematosus.
There are three main subtypes of cytotoxic hypersensitivity:
Type II reactions between members of the same species. They are
caused by isoimmunization and include transfusion
reactions after transfusion of blood incompatible in the AB0
system, haemolytic disease of the newborn due to rhesus
incompatibility and/or transplantation reaction provoked by
antibodies in the recipient directed against surface
transplantation antigens on the graft.
Autoimmune type II hypersensitivity reactions are evoked by
antibodies in the host directed against his own cell or tissue
antigens (autoantibodies). As an example may serve
autoimmune haemolytic anaemia caused by autoantibodies to
the patient's own red cells; Hashimoto's thyroiditis with
autoantibodies against thyroid peroxidase surface antigen;
idiopathic thrombocytopenic purpura manifest by platelet
destruction evoked by anti-platelet antibodies; Goodpasture's
syndrome in which complement-mediated damage to
basement membrane due to specific autoantibodies is
observed. Many diseases are caused by autoantibodies against
hormone receptors. Recently, they are also known as type V
hypersensitivity reactions. Autoantibodies directed against
receptors can have the function of agonist resulting in
stimulatory hypersensitivity and/or of antagonist leading to
the blockade of signal transmited through the receptor
occupied by such an autoantibody. The example of stimulary
hypersitivity is thyrotoxicosis where pathological stimulation
of TSH receptor occurs, whereas to the blocking
hypersensitivity belong primary myxoedema (blockade of
TSH receptor) or myasthenia gravis (blockade of
acetylcholine receptor).
subsets of mast cells.
Chronic inflammation (delayed-type of
hypersensitivity reaction)
Type IV or delayed type hypersensitivity (DTH), is most
seriously manifested when antigens (for example those of tubercle
bacilli) are trapped in a macrophage and cannot be cleared. T cells
are then stimulated to elaborate lymphokines which mediate a
range of inflammatory responses. Other aspects of DTH reactions
are seen in graft rejection and allergic contact dermatitis. DTH is
used as a general category to describe all those hypersensitivity
reactions which take more than 12 hours to develop, and which
involve cell-mediated immune reactions rather than humoral
immune reactions. Whereas allergic reactions occur within seconds
and minutes and immune complex reactions occur within several
hours to one day, DTH reactions peak at 2 to 3 days.
Unlike other forms of hypersensitivity, type IV hypersensitivity
cannot be transferred from one animal to another by serum, but can
be transferred by T cells (T
H
1 cells in mice). In humans, transfer
from a sensitized to a non-sensitized individual can be also
achieved only by T lymphocytes and, interestingly, by a low
molecular weight material extracted from them ( transfer factor).
Delayed type hypersensitivity is obviously associated with T cell
protective immunity but does not necessarily run parallel with it --
there is not always a complete correlation between delayed
hypersensitivity and protective immunity. The T cells necessary
for producing the delayed response are cells which have become
specifically sensitized to the particular antigen by a previous
encounter, and they act by recruiting other cell types to the site of
the reaction.
Three types of delayed hypersensitivity reaction are recognized:
Contact hypersensitivity and tuberculin-type hypersensitivity both
occur within 72 hours of antigen challenge, whereas
granulomatous reactions develop over a period of weeks. The
granulomas are formed by the aggregation and proliferation of
macrophages, and may persist for weeks. This reaction is, in terms
of its clinical consequences, by far the most serious type of delayed
type hypersensitivity response. The position is complicated
because these different types of reaction may overlap, or occur
sequentially following a single antigenic challenge.
The delayed type hypersensitivity reactions are probably important
for host defence against intracellular parasites such as tuberculosis
and certain viruses and are prevalent in certain disease such as
sarcoidosis, Wegener's granulomatosis, and polymyositis. In some
diseases, such as chronic granulomatous disease of childhood,
granuloma formation can lead to obstruction of vital structures
such as the esophagus or ureters. The contact dermatitis is caused
by sensitization to certain simple chemicals.
Perhaps the best known example of cell-mediated hypersensitivity
is the Mantoux reaction obtained by injection of tuberculin into the
skin of an individual in whom previous infection with the
mycobacterium had induced a state of cell-mediated immunity.
The reaction is characterized by erythema and induration which
appears only after several hours and reach a maximum at 24-48
hours, thereafter subsiding. Histologically the earliest phase of the
reaction is seen as a perivascular cuffing with mononuclear cells
followed by a more extensive exudation of mononuclear and
polymorphonuclear cells. The latter soon migrate out of the lesion
leaving behind a predominantly mononuclear cell infiltrate
consisting of lymphocytes and cells of the monocyte - macrophage
series. This contrasts with the essentially ''polymorph'' character of
the Arthus reaction.











Laboratory of Molecular
BiophysicsLaboratory
Journal 2001
Dr. J. M. McDonnell

IgE network - regulation of allergy and
inflammation.

With Hannah Gould and Brian Sutton (King's College
London).
Antibodies of the immunoglobulin E isotype (IgE) play a key role
in the immune response to host defense against parasitic infection
and in the development of allergic and inflammatory responses.
IgE elicits a range of cellular responses to antigens which are
designed to exclude parasites from the body. These include
inflammation, itching, coughing, lacrimation, bronchoconstriction,
mucus secretion, vomiting and diarrhoea; all common symptoms in
allergic disorders. In industrialized countries, where parasitic
infections are rare, the prevalence of allergic disorders are
increasing at an alarming rate; the marked increases in its
prevalence, morbidity and mortality has led to the designation of
allergy as the "number one environmental disease" (1). A recent
study found that asthma now accounts for approximately one-third
of all paediatric emergency room hospital visits. Allergy, in one
form or another, currently afflicts more than 20 per cent of the
population, with profound estimated socio-economic effects.
The effector functions of all antibodies depend on their ability to
sensitize cells for antigen-induced activation by binding to cell
surface receptors through their Fc region. IgE mediates its
biological effects through interactions with its cellular receptors Fc
RI and Fc RII. The ability to regulate these interactions offers the
potential to control the harmful effects of IgE.
In this research program we aim to determine the three-
dimensional structure of the portion of IgE responsible for binding
to its cellular receptors. We will characterize the molecular
topology of the interaction site and elucidate the physical basis of
IgE's interactions with its receptors. This information will then be
used to develop specific inhibitors of IgE/receptor interactions.








IgM
Clinical significance
IgM antibodies appear early in the course of an infection and usually
reappear, to a lesser extent, after further exposure. IgM antibodies do not
pass across the human placenta (only isotype IgG).
These two biological properties of IgM make it useful in the diagnosis of
infectious diseases. Demonstrating IgM antibodies in a patient's serum
indicates recent infection, or in a neonate's serum indicates intrauterine
infection (e.g. congenital rubella).
The development of anti-donor IgM after organ transplantation is not
associated with graft rejection but it may have a protective effect.[6]

Other points
IgM in normal serum is often found to bind to specific antigens, even in the
absence of prior immunization. For this reason IgM has sometimes been
called a "natural antibody". This phenomenon is probably due to the high
avidity of IgM that allow it to bind detectably even to weakly cross-reacting
antigens that are naturally occurring. For example the IgM antibodies that
bind to the red blood cell A and B antigens might be formed in early life as
a result of exposure to A- and B-like substances that are present on
bacteria or perhaps also on plant materials.
IgM antibodies are mainly responsible for the clumping (agglutination) of
red blood cells if the recipient of a blood transfusion receives blood that is
not compatible with their blood type.
IgM is more sensitive to denaturation by 2-mercaptoethanol than IgG. This
technique was historically used to distinguish between these isotypes
before specific anti-IgG and anti-IgM secondary antibodies for
immunoassays became commercially available. Serum samples would be
tested for reactivity with an antigen before or after 2-mercaptoethanol
treatment to determine whether the activity was due to IgM or IgG.
[.
Activities of IgG, IgM
antibodies and the C3b
inactivator-cleaved third
component of complement in
macrophage phagocytosis
B. Wellek, H. Hahn, W. Opferkuch
Abstract
Phagocytosis of SRBC by guinea-pig peritoneal macrophages is
enhanced by opsonizing IgG antibody alone. IgM antibody requires the
presence of bound C3. Treatment of C3b coated SRBC with purified C3b
inactivator (yielding EAIgM C1423d) does not reduce attachment to, and
phagocytosis by, peritoneal macrophages. This finding suggests the
existence of a C3d receptor on peritoneal macrophages. EC43b
intermediates which have been produced by removing IgM antibody by
mercaptoethanol treatment and by subsequent removal of C1 and C2, are
phagocytosed despite the absence of IgM antibody. Furthermore,
treatment of EC43b with C3b inactivator does not change phagocytosis.
Thus, IgM antibody does not appear to be a necessary prerequisite for the
stimulation of phagocytosis, C3b or C3d alone being sufficient.
Background
Selective immunoglobulin M (SIgM) deficiency is a rare form of
dysgammaglobulinemia characterized by an isolated low level of serum
immunoglobulin M (IgM). Reported IgM concentrations in SIgM deficiency
vary from 40 mg/dL (though some sources say 20 mg/dL) to undetectable
levels (reference range 45-150 mg/dL in adults).[1] Recent series report
IgM levels of 29.78.7 mg/dL (meanSD) for adults and 16.513.8
(meanSD) in children.[2, 3] In this context, remember that 2.1% of
"normal" individuals have values < 2 SD below the mean and that values in
children must be compared with reference range values for age.[4] The
levels of other immunoglobulin classes are within reference ranges.
SIgM deficiency may occur as a primary or secondary condition.
Secondary SIgM deficiency is much more common than primary SIgM
deficiency and may be seen in association with malignancy, autoimmune
disease, gastrointestinal disease, and immunosuppressive treatment.
Some patients are asymptomatic, whereas others (often infants and small
children) develop serious infections. Patients may develop prolonged or
life-threatening infections caused by both encapsulated bacteria and
viruses, especially in infancy. In older children and adults, SIgM deficiency
is usually discovered during the investigation of other conditions, such as
autoimmune disease or malignancy.
Serum immunoglobulin levels are controlled by intricate immunological
regulatory mechanisms, and heterogeneity is believed to exist in the
pathogenesis of SIgM deficiency. Little is known about the pathological
features of SIgM deficiency at a cellular level, given that the condition is so
uncommon. Processes that control the survival of IgM in the circulation
and may otherwise regulate its concentration in serum have not been well
described; alterations in clearance mechanisms, in addition to altered
production of IgM by lymphocytes, may contribute to selective deficiency of
this immunoglobulin isotype.

Pathophysiology
The cause of SIgM deficiency is unknown. Increased regulatory T-cell
activity specific for IgM has been described.[5] The absence of IgM in the
presence of normal levels of immunoglobulin G (IgG) and immunoglobulin
A (IgA) has yet to be explained, as this appears to contradict the theory of
sequential immunoglobulin gene rearrangement. Normal mature B cells
are expected to have IgM and immunoglobulin D (IgD) on their surfaces,
and, with proper stimulation, rearrange their immunoglobulin genes to
switch from expressing IgM to IgG, IgA, or immunoglobulin E (IgE).
Having normal levels of IgG and IgA in the face of low IgM is thus
counterintuitive. One could speculate that failure to regenerate B-cell
precursors could lead first to depletion of IgM, with gradual loss of IgG and
other isotypes occurring later as class-switched memory B-cells and
plasma cells fail to be replaced. This hypothesis has not been tested, and
few studies are available to determine whether only the serum IgM level is
low or whether the number of B cells with surface IgM is also decreased in
patients with selective IgM deficiency. Gradually, current state-of-the-art
laboratory technology is being applied in studying patients with SIgM
deficiency, though much remains to be learned.
The currently available literature suggests a heterogeneous population of
patients of SIgM deficiency. Some patients are capable of normal antibody
responses of other immunoglobulin classes following specific
immunization, whereas others respond poorly. Certain patients with
decreased helper T-cell activity have been described.[6] Cell-mediated
immunity appears to be intact, but an insufficient number of detailed
studies are available to confirm this. Suggested etiologies include rapid
isotype switching of B cells from production of IgM to production of other
isotypes and hypercatabolism of IgM.