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Functions ofblood group antigens 293
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Table20.2 Diverse functions ofblood group antigen proteins
Blood group Alternative name(s) Function
Cartwright (Yt) ACHE Acetylcholinesterase
Chido/Rodgers (CH/RG) C4B/C4A CFB and CFA complement components adsorbed from plasma
Colton (Co) AquaporinCromer (Cr) Decay accelerating factor,CD55 Promotes the degradation of C3 and C5 convertases
Dombrock (Do) DOK ADP- ribosyltransferase ectoenzyme
Duffy (Fy) DARC Promiscuous chemokine receptor, clears proinflammatory cytokines, and also
Gil AQP3 Water channel that also transports other small molecules, including glycerol
Jr CD338, JR, ABCG2 ATP- dependent transport protein with broad substrate specificity
Kell (K) KEL Zinc- binding neutral endopeptidase; endothelin- 3 converting enzyme that
Kidd (Jk) UT1 Urea transporter important in renal urea concentrating ability
Knops/McCoy (Kn/McC) C3b/C4b receptor (CD35),
complement receptor type 1
Kx XK Possibly a neurotransmitter transporter; deficiency causes neuroacanthocytosis
Lan ABCB6 Binds heme and porphyrins and has a role in ATP-
Emm PIGG PIGG encodes for a transferase, GPI- ethanolaminephosphate transferase II,
MAM EMP3 EMP3 stabilizes the cell surface signaling molecule CD44. EMP3 and CD44 play
1 (AQP- 1) Water channel
affects circulating neutrophil count
cleaves big endothelin- 3 to bioactive endothelin- 3
Binds C3b and C4b and facilitates immune clearance
or McLeod syndrome
dependent uptake into
mitochondria
which adds ethanolamine phosphate (EtNP) to the second mannose in a
GPI- anchor
an important role in red cell production.
be used to confirm the Kidd- null phenotype in suspected
cases and as a method to screen blood donors for this rare
phenotype.
Table 20.2 lists blood group antigens associated with
functions other than those discussed in previous items. As
indicated, proteins bearing blood group antigens have a
broad diversity of functions. Some, such as the proteins that
bear the Kidd and Colton blood group antigens, are transporters. Others, such as those that bear the Cartwright and
Kell antigens, are ectoenzymes. In addition, erythrocytes
bear receptors for complement components and chemokines.
The degree to which polymorphisms and deficiency of these
proteins contribute to human disease continues to be further
explored.
Summary
Proteins that bear blood group antigens have diverse functions, and some proteins, such as AE1, encompass several
functions within a single protein molecule. Abnormalities
of these proteins, in the form of either deficiencies or mutations, can lead to red cell disorders, such as hemolytic anemia,
or have more far- reaching effects, as in the association of
Kx deficiency with neuroacanthocytosis and mutations of
AE1 with renal tubular acidosis. Finally, these proteins
undoubtedly contribute both to normal physiology and to
the pathophysiology of human diseases, including sickle cell
anemia, malaria, and perhaps others.
Further reading
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1 channel
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Chapter21
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disorders
Autoimmune hematological
Drew Provan1 and John W. Semple
1
Centre for Haematology, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
2
Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden
3
Clinical Immunology and Transfusion Medicine, Office of Medical Services, Region Skåne, Lund, Sweden
4
Departments of Pharmacology and Medicine, University of Toronto, Toronto, ON, Canada
Introduction, 299
The immune system, 299
The spectrum of autoimmune diseases, 305
Role of genetic factors, 305
Mouse models of autoimmune disease, 307
Human studies,
Introduction
307
2,3,4
Immune thrombocytopenia as a
hematological model of autoimmune disease, 309
Targeted versus untargeted therapies for autoimmune disease, 313
Novel therapies for the treatment of ITP, 316
Conclusions, 317
Further reading,
317
which may result in disease. Factors that play a role in this
process include immune dysregulation, genetic factors,
Autoimmune diseases are disorders where antibodies or
cells react against self- antigens to cause disease, at which
point an adaptive immune response is mounted against the
and triggering events such as environmental factors (e.g.
infection). We discuss all of these after briefly reviewing the
structure and function of the immune system.
self- antigen or antigens. This results in clearance of the antigen from the body. The normal adaptive response results
in complete removal of the non- self- antigens, whereas in
autoimmune disease, there is incomplete clearance of the
antigen, which leads to the perpetuation of the immune
response. Autoimmune disorders occur in about 5–7% of the
population, although many individuals have no symptoms.
In all, there are more than 70 different disorders, most of
which are uncommon, apart from rheumatoid disease and
autoimmune thyroiditis. Autoimmune diseases are clinical
syndromes mediated by the activation of T or B lymphocytes, or both, in the absence of infection or other discernible
cause. Until recently, although we could describe the pathological features of autoimmune disease, we had little idea as
to their actual cause. Through the development of animal
models and the identification of target genes, we have gained
considerable insight into the pathogenetic basis of these
complex diseases. Autoreactive cells may affect virtually any
body tissue, including blood, and blood disorders in which
autoantibodies are found include cytopenias such as autoimmune hemolytic anemia, immune thrombocytopenia (ITP),
and autoimmune neutropenia, in addition to coagulation
disorders such as acquired hemophilia.
Although autoimmune disease is clinically and pathologi-
cally diverse, the common end result is damage to antigen,
The immune system
The immune system comprises cells and molecules whose
main role is defense against invading pathogens. The two
principal components are the innate immune system, comprising skin, mucous membranes, neutrophils, macrophages/
dendritic cells that serve as antigen- presenting cells (APCs)
and other scavenging cells, in addition to the complement system and natural killer (NK) cells; and the adaptive immune
system, which involves exclusively B and T lymphocytes
(Figure21.1). The B- cells are responsible for plasma cell
production and secretion of antibodies, and this process is
critically dependent on T- cells. Key features of the adaptive
system include antigen receptor diversity, antigen specificity,
and immunological memory. This is in sharp contrast to the
innate system, which lacks these features.
The innate immune system
Despite varied challenges by many antigens, because the
innate system lacks the ability to develop immunological
memory, the responses remain the same throughout life. In
evolutionary terms, the innate system probably developed
before the adaptive system. The innate immune system is
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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299
300 Molecular Hematology
Microbes
Time after infection
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Adaptive immunityInnate immunity
Epithelial
barriers
Phagocytes
NK cells
0
Figure21.1 Innate and adaptive immune systems. The innate system comprises physical barriers (e.g. skin) along with scavenger cells, while
the adaptive system comprises B and T lymphocytes. Temporarily, the innate system is the immediate first line of defense but lacks specificity.
Theadaptive system comes into play later and possesses immunological specificity and memory. From Abbas AK, Lichtman AH, Pober JS. (2000)
Cellular and Molecular Immunology, 4th edn. © 2000, with permission from Elsevier.
6
Hours
composed of physical, chemical, and cellular components
that act together to mediate the first line of defense against
invading microorganisms. These components are intimately
linked with inflammatory processes and ultimately lead to
B lymphocytes
T lymphocytes
12
Antibodies
Effector T cells
Days
531
able to migrate to lymph nodes, process antigen, and present
this to T-
cells in conjunction with major histocompatibility
complex (MHC) molecules, of which there are two classes,
class I and class II.
the removal of most of the infectious organisms encountered
by a host. The innate immune response activates quickly
(within seconds) after exposure to foreign infectious agents
and is antigen non- specific in that there is no memory associated with the immunity. These characteristics distinguish
the innate immune system from the adaptive immune
response, which is mediated exclusively by B- and T- cells, is
slower to activate and is exquisitely antigen- specific, generating memory with subsequent exposure to the stimulating
antigen.
APCs are key players of innate immunity and physically
link innate and adaptive immune responses by presenting
antigens to T-
cells. APCs additionally possess surface receptors for antibody (immunoglobulin) and complement.
Microorganisms opsonized by antibody and/or complement
are recognized by these receptors, phagocytosed, and broken
down within the interior of the APCs. Within cells such as
neutrophils, killing and digestion of the pathogen involves
the generation of superoxide and hydroxyl radicals, nitric
oxide, and proteolytic enzymes. In addition to the removal of
pathogens, the innate system also plays a role in the removal
of dead cells and remodeling of tissue during healing. Cells
undergoing programmed cell death (apoptosis) express molecules such as phosphatidylserine on their surface, targeting
their removal. Dendritic cells also play a key role in innate
immunity, and activation of dendritic cells occurs following
exposure to heat- shock proteins, interferon (IFN)- α, and
other stimuli. Dendritic cells are professional APCs that are
The adaptive immune system
Two requirements of an effective immune system are (i) the
ability to recognize millions of potential antigens and (ii) the
prevention of self- reacting lymphocytes from causing tissue
damage. The former is achieved through irreversible somatic
recombination of immunoglobulin and T- cell receptor (TCR)
genes, generating many millions of different antibody and
TCR molecules.
B- and T- cells possess antigen receptors on
theirsurface
The antigen receptor of the B- cell is an immunoglobulin and
that of the T- cell is the TCR. These molecules are expressed
on their respective cell surfaces and interact with antigen,
either as native (immunoglobulin) or processed (TCR) antigens. The TCR is a transmembrane protein and consists of a
heterodimer of either αβ or γδ subunits. TCRs, like immunoglobulins, contain hypervariable regions and in evolutionary
terms, the two receptors are probably related. Unlike TCRs,
antibody molecules are both expressed on the B- cell surface
and secreted into body fluids. One feature that both receptors share is the ability to generate enormous diversity
through irreversible recombination of germline variable (V),
diversity (D), and joining (J) region segments in addition to
random mutations within the rearranged genes. Immunoglobulin molecules possess two key regions: the hypervariable
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Autoimmune hematological disorders 301
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region (antigen binding) and the Fc portion at the C- terminal
end which, as outlined above, is recognized by the Fc receptor (e.g. FcγR) on macrophages. Antibodies may be of the
IgG, IgA, IgM, IgD, or IgE class, with subclasses within some
of the groups (e.g. there are four IgG subclasses and two IgA
subclasses). Having such enormous diversity ensures that
there is an antibody for every potential antigen encountered,
but the downside of this extreme diversity is that antibodies
are generated that recognize self- antigens (autoantibodies),
and it is likely that in normal healthy subjects, autoantibodies are generated against a wide variety of antigenic targets.
Since autoimmune disease is not common, there must exist
a mechanism for removing or suppressing self- reacting
antibodies. In effect, an immunological lack of responsiveness or tolerance must exist, whereby self- reactive cells are
prevented from causing damage. Recent research has shown
this to be the case.
The major histocompatibility complex
Class I MHC molecules comprise human leukocyte antigen
(HLA)- A, - B, and - C, and class II molecules consist of
HLA- DP, - DQ, and - DR. Class II molecules are responsible
for the presentation of antigen to the TCR on CD4+ helper
T- cells.
NK cells have receptors for the immunoglobulin Fc region
and are responsible for antibody- dependent cellular cytotoxicity following FcγR linkage of NK cells and antibodyopsonized targets. In addition, NK cells can effect killing
using killer- activating receptors, which recognize specific
molecules on nucleated cells. An inhibitory molecule (killer
inhibitory) recognizes MHC class I on nucleated cells, preventing killing, but if MHC class I is lost (e.g. during infection
of the cell by virus or after malignant transformation), the
nucleated cell is recognized as being abnormal and is therefore targeted for destruction.
local. In order to exert their effect, cytokines interact with
specific receptors and promote signal transduction. Their
main routes of action are via the Janus kinase (JAK)/STAT
and Ras/MAP pathways. The cytokine profile may be proinflammatory or anti- inflammatory and the cytokine balance
will dictate whether a helper T- cell clone engages in a Th1 or
Th2 response. In general, Th1 responses are effective against
intracellular pathogens and Th2 responses aid B- cells.
Cytokine profiles of Th1 and Th2 responses
(Table21.1)
APCs, and in particular dendritic cells, are responsible for
T- cell differentiation toward the Th1 or Th2 phenotype; the
cytokine IL- 12 plays a key role in the Th1 response, and
IL- 4in the Th2 response. Since cytokines play such a key role
in orchestrating an effective immune response, it is likely
that dysregulation of cytokine levels may induce an autoimmune response in some disorders. This has been shown to be
the case in experimental models and also in human disease.
For example, transfection of the gene for IFN- γ on the insulin
promoter has been shown to induce inflammation within
the pancreas, with aberrant expression of MHC class II and
the development of diabetes. In addition, proinflammatory
cytokines, such as IL- 12, TNF and IFN- γ, can induce organ-
specific autoimmunity.
Because of limitations of space, the role of complement is
only very briefly discussed here. Following infection, cells
of the immune system migrate toward the affected site.
Complement component C3b coats the pathogen surface.
The molecules C3b, C3a, C4a, and C5a, in addition to neutrophil chemoattractant, trigger mast cells to release histamine.
This induces smooth muscle contraction and increased
Table21.1 Cytokine profiles ofTh1 andTh2 responses
Soluble molecules: cytokines orchestrate
theimmune response
The innate system relies on a complex network of soluble
molecules, such as cytokines and complement components,
that coordinate the entire immune response. We discuss
these briefly here since they are implicated in the pathogenesis of autoimmune disease.
Cytokines are mediators secreted by one cell that influence
the behavior of other cells. Most cytokines are soluble, apart
from interleukin (IL)- 1 and tumor necrosis factor (TNF)- α,
which have membrane- bound forms. Cytokines are small
molecules of around 15–25 kDa whose actions include the
promotion of cell growth, inflammation, immunity, and
repair of tissues. These molecules are responsible for the
regulation and orchestration of the entire immune response.
Their effects are short- lived and their actions are largely
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Th1 response
(activates macrophages)
IL- 2 –
IL- 3 –
– IL- 5
– IL- 6
– IL- 10
– IL- 13
TNF- α –
TNF- β TNF- β
IFN- γ –
GM- CSF GM- CSF
These are the principal cytokines involved in generation of Th1 and
Th2 responses. Imbalance in Th1 or Th2 cytokines may play a role in
the development of autoimmune disease, allergy, and other disorders.
Th2 response
(deactivates macrophages)
IL- 4
302 Molecular Hematology
Cortex
Thymus gland
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blood vessel permeability, allowing neutrophils to pass
through the blood vessel walls more easily, an essential
requirement for an effective innate response.
T- cells (Figure21.2)
These develop within the thymus. T- cells bearing αβ TCRs
recognize processed antigen presented to them by APCs,
including dendritic cells. Within the thymus, T- cells are
selected in order to prevent autoreactivity; that is to say,
mechanisms exist whereby T- cells are prevented from
reacting with self- antigens. Positive selection occurs when
T- cells express TCRs that are able to interact with MHC
complexes on thymic cortex epithelial cells. The effect of
positive selection is to prevent apoptosis. T- cells expressing
TCRs with high or low affinity for self- molecules are negatively selected and undergo apoptosis.
Immunological tolerance prevents damage
toself-
antigens
Tolerance defines the body’s ability to recognize, but not
react with, self- antigens, while retaining the ability to
respond to non- self- antigens. This process involves the
negative selection of T- cells, as outlined above. In addition,
the process involves the control of autoreactive B- cells. The
process of selecting T- cells and B- cells in the thymus and
bone marrow respectively is known as central tolerance. For
autoreactive lymphocytes that escape into the periphery, there
are additional peripheral tolerance mechanisms to provide a
safety net for unwanted autoreactivity.
T- cell tolerance: central mechanisms
Immature T- cells from the bone marrow migrate to the thymus, where they complete their development. The T- cells
within the thymus interact with MHC molecules in low- or
high- affinity interactions. If the TCRs have a low affinity for
the peptide (e.g. self- peptide), they receive apoptotic signals
and die within the thymus. Likewise, T- cells participating
in high- affinity interactions have a similar fate and it is
only when the interaction is of intermediate affinity that
the T- cells survive and migrate to the periphery, a process
termed positive selection. In general, positive selection occurs
when CD4+CD8+ double- positive T- cells interact with TCR–
MHC–peptide complexes. For most T- cells, the interaction
is of low avidity and the T- cells die before leaving the thymus.
A minority of CD4+CD8+ T- cells have intermediate avidity
reactions and hence these cells survive, after which they mature
into single- positive CD4+CD8− and CD4−CD8+ cells. CD4+
T- cells, and are the main effectors of autoimmune disease.
Cortex Medulla
MHC
Cortical
epithelial cell
Medulla
CD8 and CD4
T cell
Figure21.2 T- cell selection within the thymus. T- cells undergo positive and negative selection. CD4+CD8+ T- cells interact with MHC–peptide
complexes. Depending on the strength of the interaction, the T- cells either undergo apoptosis (the majority) or survive and leave the thymus
(theminority). Reproduced with permission from Delves PJ, Roitt IM. (2000) The immune system. First of two parts. New England Journal of
Medicine, 343, 37–49.
CD8
T cell
CD4
T cell
Negative
selection
Apoptosis
Positive
selection
or macrophage
T-cell
receptor
Apoptosis
T cell
Dendritic cell
T-cell
receptor
CD8 or CD4
Positive
selection
CD8 or CD4
MHC
T cell
Surviving
cells leave the
thymus
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