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Immunodeficiency –
Immunodeficiency occurs when one or more components of the immune response are
defective
...
These can be broadly
classified in to primary immunodeficiency and secondary immunodeficiency
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their effects are variable
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This is quite rare
...
This may be the result of
another infection, environmental factors such as starvation or as an adverse consequence to
medical intervention
...

Primary immunodeficiency –
Patients with this type of immunodeficiency are identified as having recurrent infection with
the same or similar pathogen and this allows the identification of which ever part of the
immune response which is deficient
...

In contrast a history of persistent fungal skin infections such as cutaneous candidiasis or
recurrent viral infections is more suggestive of a defect in host defence mediated by T
lymphocytes
...

Immunodeficiency can be caused by defects in either the adaptive or the innate immune
system
...
DiGeorge’s syndrome is where you have variable
numbers of T and B cells also making you susceptible to general infections
...
Selective IgA
syndrome means you have no IgA synthesis and leaves you susceptible to respiratory
infections
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this shows the
pathways leading
to circulating naïve
T and B cells
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Immunodeficiency
can also be caused
by mutations in
genes in the
thymus epithelium
that impair thymus
development and
thus T cell
development
...

These diseases reflect the key role which the T cell would normally play in the infection
...

Patients with a T cell deficiency lack T-cell dependent antibody responses and cell-mediated
responses
...
This deficiency causes a condition
called sever combined immunodeficiency (SCID)
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Patients
with SCID
...
This means that patients have a defect in the signalling of several cytokines
including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
...

A mutation within the Jak3 gamma chain causes the same condition however B cells are
able to develop normally in this instance
...
It has also been shown to be important in T cell maturation and trafficking
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However,
maintenance of CD8 T cells is defective
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SCID due to defects in antigen receptor gene arrangement: RAG
Another set of defects leading to SCID are those which cause failure of DNA rearrangement
in developing lymphocytes
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This
leads to a complete lack of T and B cells, NK cell development is not impaired
...
This means that they are able to make a small
amount of RAG protein and so a small amount of V(D)J recombination is able to take place
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In addition to increased
susceptibility to opportunistic infections, the patient will also have symptoms similar to that
seen in a graft vs host disease
...
The clinical feature suggest that these T cells are
autoreactive and ergo cause the graft vs host disease symptoms
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Radiation sensitive: These patients have very few B and T cells due to failure of antigen
receptor gene rearrangement
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A different mutation found in some people with autosomal SCID is in the protein Artemis
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These two form a complex which acts to open
the hairpin structures to allow the formation of the VJD joints to complete the VDJ
recombination
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SCID due to defects in TCR signalling –
There are several gene defects which interfere with T cell receptor signalling
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Others who have defects in cytosolic protein tyrosine kinase ZAP-70 which usually works to
transmit signals from the T cell receptor have a loss of CD8+ T cells emerging from the
thymus and CD4 cells do not respond to stimuli
...

WAS – Wiskott-Aldrich syndrome –

Caused by a defect in the WAS protein gene on chromosome X
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WASp is a key regulator of lymphocyte development through transduction of TCR signals:
several signalling pathways down stream of TCR activate WASp
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Immunodeficiency due to defects in thymic function that block T cell development
In mice this is characterised by those with no hair and SCID, these are nude mice
...
This
encodes for a transcription factor which is selectively expressed in the skin and the thymus
...
In patients with this mutation, the lack of thymic function prevents
thymic-dependant T cell development
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DiGeorge syndrome –
This is a condition where the thymic epithelium fails to develop normally
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The smallest deletion can be 24 genes
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Deletion of one cope of the gene means that patients are haplosufficient → absences or
incomplete thymus development with impaired T cell mediated immunity and T cell
dependent antibody production
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They suffer from severe immunodeficiency
...
The antigen presenting cells in these individuals also lack MHC2 and so cannot
present antigen to the few CD4 T cells which have developed
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This is caused by mutations in gene regulator proteins required for transcriptional
activation
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MHC 1 deficiency –
This deficiency is linked to chronic respiratory bacterial infections and skin ulceration with
vasculitis
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Individuals have normal levels of mRNA encoding MHC1 molecules and normal production
of the MHC1 protein but very few of the proteins reach the cell surface
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This deficiency results in a lack of alpha:beta CD8 T cells but not gamma:dalta CD8 T cells as
their development is independent of the thymus
...
This is surprising as it is thought that MHC1 is crucial for
clearing infections as this presents the viral antigen to the CD8 cells for combatting
infection
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Defects in B cell development –
B cell development deficiencies are associated with inability to clear extracellular bacteria
such as staphylococci, streptococci and some viruses such as enteroviruses (single stranded
RNA, hands foot and mouth, meningitis)
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Bruton’s X-linked agammaglobulinemia – (XLA)
Absences of serum antibody usually detected a few months after birth due to recurrent
infections with pyogenic bacteria such as streptococcus pneumoniae
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This is a tyrosine kinase and member of the Tec family of kinases
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Without BTK no signal can be transduced and so the development of the B cell is arrested
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Babies are born with high levels of maternal IgG, which is actively transported across the
placenta from the mother during gestation
...
Thus, IgG
levels are low from about the age of 3 months to 1 year, which can lead to susceptibility to
disease
...
The protein products of genes known
to be mutated in the relevant human
immunodeficiency diseases are indicated in red
boxes
...

Note that the defect in cytoskeletal function in
Wiskott–Aldrich syndrome (WAS) affects immunecell function at many steps in this schema, and is
not included in the figure for the sake of clarity
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Hyper IgM syndrome These patients are susceptible to recurrent and severe infections and in some types of hyper
IgM syndrome opportunistic infections and an increased risk of cancer as well
...
They will have reduced levels of IgD, G, E and A and this indicates an impairment of
class switching
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The affected protein is called CD40
ligand and binds to CD40 receptors on B lymphocytes
...

This means that although the B cells are normal, they are not able to engage their CD40
receptor which is essential for germinal centre formation and the induction of isotype
switching
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The defective cellular immune response is thought to be as a result of the inability of the T
cells to deliver an activating signal to infected macrophages by engaging the CD40 on these
cells
...

Chromosome 20 also encodes for CD40, so mutations here also result in an autosomal
recessive variant of hyper IgM syndrome
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They also show hyper IgM syndrome
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Lymphoid tissues in patients with CD40 ligand
deficiency, which manifests as a hyper-IgM syndrome,
are devoid of germinal centers (top panel), unlike a
normal lymph node (bottom panel)
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Photographs courtesy of
R
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Perez-Atayde
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This is
associated with a milder form of immunodeficiency
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The B cells in these patients
fail to switch antibody isotype and have much reduced somatic hypermutation
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AID deficiency only causes the failure of antibody responses, whereas deficiency of other
proteins is associated with defects in both B- and T-cell function
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Another predominantly humoral immunodeficiency is common variable immunodeficiency
(CVID)
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At least

some cases are familiar
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This is
not as severe as other immunodeficiencies and can go undiagnosed in to early adulthood
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This is the cytokine receptor for BAFF
which is secreted by dendritic cells and provides co-stimulatory and survival signals for B-cell
activation and class switching
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ICOS is essential in
providing help to B cells in the later stages of development such as during differentiation,
inducing class switching and forming memory cells
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There is a defect in STAT3 in autosomal dominant variant
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Genetic deficiencies of cytokine pathways
Defects may be in cytokines or receptors
Increased susceptibility to intracellular pathogens normally controlled by NK/ILC1/TH1 cells
(e
...
, Mycobacteria)
Mutations impair or abolish function of IL-12 or IFN-g, cytokines involved in
development/function of type 1 cells
IL-12p40/IL12Rb1 mutations also impact on TH17/ILC3 responses due to IL-23 signalling
Also, mutations in STAT1 impair IFN-g receptor signalling, again resulting in increased
susceptibility to intracellular bacteria
Shown are pathways in IL-12, IL23, and IFN-γ signaling for which
inherited defects have been
described
...

Also, because STAT1 is activated is by the receptors of type II interferon (IFN-γ) and type I
interferon (IFN-α and IFN-β, not shown), defects in STAT1 result in impaired antibacterial
and antiviral immune defense, whereas deficiency in either of the IFN-γ receptor subunits
(IFN-γR1 or IFN-γR2) primarily results in impaired defense against intracellular bacteria
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*Deficiencies of IL-12p40 and IL-12Rβ1 also result in TH1/ILC1/NK cell deficits
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Immunodeficiency due to inherited defects in DC development
Defects in GATA2 and IRF8 identified in humans
Autosomal dominant mutation of GATA2 most common; associated with progressive loss of
all DC subsets and monocytes as well as reduced numbers of B and NK cells, causing diverse
immune defects/pathogen susceptibilities
For IRF8, mutations in the TF DNA-binding domain have been observed; two forms found
with varying cell type loss and susceptibility to a range of opportunistic infections

Defects in the early components of the alternative
pathway and in C3 lead to susceptibility to
extracellular pathogens, particularly pyogenic
bacteria
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Deficiency of
mannose-binding lectin (MBL), the recognition
molecule of the mannose-binding lectin pathway,
is associated with bacterial infections, mainly in
early childhood
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Immunodeficiency in Complement components –
Complement deficiencies overlap with deficiencies in antibody production
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peumoniae, emphasising the important role of C3 as an opsonin that

promotes phagocytosis of bacteria
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This indicates that defence against bacteria which can
survive intracellularly is mediated by extracellular lysis by the membrane-attack complex
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The early components of the classical complement pathway are particularly important for
the elimination of immune complexes and apoptotic cells which can cause significant
pathology in autoimmune diseases such as systemic lupus erythematosus
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People lacking
decay-accelerating factor (DAF) and CD59 which protect the body’s cell surfaces from
complement activation, destroy their own RBCs
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A more striking consequence of the loss of complement
regulatory protein is seen in patients with C1 inhibitor defects
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As well as inhibiting the serine proteases C1r
and C1s, and thus regulating the initiation of the classical pathways of complement
activation, C1 inhibitor inhibits two serine proteases that participate in the contact
activation system of blood clotting factor – factor XIIa (activated Hageman factor) and
kallikrein
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These mediators are bradykinin produced by the cleavage of high molecular
weight kininogen by kallikrein and the C2 kinin produced by the activity of C1s on C2b
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MBL deficiency may also be
associated with a mild
immunodeficiency with an excess of
bacterial infection in early childhood
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Inherited deficiencies of neutrophil production (neutropenias) are classified either as severe
congenital neutropenias or as cyclic neutropenias
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2x10^9/L of blood when it should normally be 3-5
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Cyclic neutropenia is a dominantly inherited disease in which neutrophils numbers fluctuate
from near normal to very low or non, with an approximate cycle of 21 days
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Mutation in human neutrophil elastase ELA2, a component of primary granules; altered
targeting of defective gene product causes apoptosis of developing cells, cause cyclic
neutropenia and also cause a significant fraction of dominant severe congenital
neutropenia
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Heterozygous mutations in the oncogene GFI1 which encodes a transcriptional repressor
have been detected in three patients with neutropenias
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Closer analysis revealed that mutation in mouse Gfi1 affects the expression of ELA2
providing a link between these two genes in a common pathway of myeloid celldifferentiation
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Defects in the migration of phagocytic cells to extravascular site of infection can cause
serious immunodeficiency
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The first stage is rolling adherence of leukocytes to endothelial cells through the binding of a
fucosylated tetrasacccharide ligand known as sialyl-Lewis X on the leukocyte to E-selectin
and P-selectin on endothelium
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The third and final stage is the transmigration of leukocytes through the endothelium along
gradients of chemokines originating from the site of tissue injury
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Reduced
rolling adhesion has been described in patients with a lack of sialyl-Lewis X antigen caused
by a deficiency in a putative GDP-fucose transporter that participates in fucosylation during
sialyl-LewisX biosynthesis
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A third genetic defect that prevents neutrophil migration was identifies in the Rac2 gene
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All these deficiencies lead to infections which are resistant to antibiotic treatment and that
persist despite an apparently effective cellular and humoral adaptive response
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Immunodeficiency has been noted as a consequence of defects in components of TLR
signalling
“Cold” infection: recurrent severe infections with pyogenic bacteria that cause little
inflammation due to mutations in MyD88 or IRAK4 genes (may also impact on IL-1 family)
NEMO deficiency blocks TLR-and IL-1 receptor family signalling by blocking activation of NFkB
Amongst human TLRs, only defects in TLR3 have been associated with overt
immunodeficiency (cause herpes simplex encephalitis due to failure of cells in the CNS to
produce type I interferons)
Chronic granulomatous disease (CGD): defect in production of reactive oxygen species,
which facilitate microorganism killing – high susceptibility to bacteria/fungi infections and
form granulomas as a result of an inability to kill bacteria ingested by phagocytes
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Deficiencies in glucose6-phosphate dehydrogenase (G6PD) and myeloperoxidase can also result in disease but
with less severe phenotype

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