shawk Immunodeficiency disease Caused by defect in various components of immune system and results from a genetic or developmental defect or acquired factors in the immune system Immune deficiency occur in two different ways ID: 914681
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Slide1
IMMUNE DEFICIENCY
Dr. Refif Al-
shawk
Slide2Immunodeficiency disease:
Caused by defect in various components of immune system and results from a genetic or developmental defect or acquired factors in the immune system
Slide3Immune deficiency occur in two different ways
Primary I.D.
-
usually genetic, congenital
Secondary I.D.
-
Acquired (infection ,therapeutic treatments, cancer & malnutrition)
Slide4Mechanisms of Immunodeficiency
Loss or reduction of:
Cell type
Cell numbers
Cell function
Slide5Loss of Cell Function
Receptors
Cell signaling
Cytokine production
Ig
production
Co-stimulation impairment
Intracellular killing
Extravasation
impairment
Slide6Slide7Characteristics seen in many immune deficiency diseases include the following:
Recurrent or chronic infections
Inability to clear infectious agents after standard antibiotic therapy
Unusual infectious agents
Slide8Hematopoiesis
Slide9Primary Immunodeficiency
Myeloid lineage
Congenital
agranulocytosis
Leukocyte-adhesion deficiency
Chediak-higashi
syndrome
Lymphoid lineage
Severe combined immunodeficiency (SCID)
B cells
Agammaglobulinemia
Hypogammaglobulinemia
Specific
Ig
Deficiencies
T cells
DiGeorge
Syndrome
Wiskott
Aldrich Syndrome
Complement or its Regulation
· Hereditary
angoedema
Defect in
phagocytic
cells (Myeloid):
(
phagocytes,
neutrophils
)
Defects are significant because of their key role in innate and adaptive I.R.
affect both ability to kill
microb
( Chronic granulomatous disease,
Chediak
-higashi syndrome )
interactions with other cell
(Leukocyte adhesion defect 1)
Slide11Defects in Myeloid Lineage
Progenitor
Progenitor
Slide12Chronic
Granulomatous
Disease (CGD)
Defect in enzymes and
microcidal
molecules (
NADPH
oxidase
; failure to generate superoxide anion & other O2 radicals)
So the microorganisms will be ingested but not killed
Symptoms : recurrent infections with
catalase
- positive bacteria and fungi specially
Staphylococcus
aureus
Slide13Chediak
- Higashi Syndrome
Normal levels of these enzymes(digestive)
Defect in organelle membrane which inhibits normal fusion of
lysosomes
Fail to
destroy ingested microbes
Symptoms : Recurrent infection with bacteria (
chemotactic
and
degranulation
defects, absent NK activity, partial
albinism
)
Slide14Leukocyte Adhesion Defect 1
( LAD-1)
Absence of CD 18 – common
β
eta chain of leukocyte integrin, and become
un able to migrate
Symptoms : Recurrent and chronic infection , fail to form pus
Lymphoid lineage
B cells
X-linked (
Bruton
)
Agammaglobulinemia
X-linked hyper-
IgM
syndrome
Specific
Ig
Deficiencies (Selective
IgA
deficiency)
Common variable immunodeficiency
T cells
DiGeorge
Syndrome
Wiskott
Aldrich
Syndrom
Bare Lymphocyte syndrome/ MHC II deficiency
MHC I deficiency
Complete functional B and T cell deficiency
Sever combined immunodeficiency (SCID)
Defect In
Humoral
Immunity
These B-cell defects are responsible for the majority (more than 80%) of human immunodeficiency diseases
Patients with common defects in B-cell function have
pyogenic
infection :
pneumania
otitis
media
sinusitis
Slide19Defects in B-cell function due to
Early B cell maturation blocked
Terminal differentiation of B cell blocked
Isotype
switching dose not occur
T-cell to B-cell is defective
Slide20Defects in B cell development
Progenitor
Progenitor
Slide21Early B Cell Maturation Fails In
X-linked (
Bruton
)
Agammaglobulinemia
Genetic disease that only affects males which results in few or no B cells in their blood or lymphoid tissue
The genetic defect in gene
Bruton
tyrosine
kinase
(BTK)
an enzyme that is critical to early differentiation of B-cells into
plasma cells
which ultimately are responsible for producing
immunoglobins
Because of abnormally low
immunoglobin
levels, the patient is susceptible to certain infections
(encapsulated bact.)
such as:
Meningitis
Recurrent ear infections
Chronic sinus/upper respiratory infections
Treatment : monthly
gammaglobulin
replacement, antibiotics
Slide22Otitis
media
Slide23Terminal Differentiation Of B Cells Fails In
Selective
IgA
Deficiency
Most common immunoglobulin deficiency affecting 1 to 2 per thousand individuals
Main physical characteristic is a
severe reduction in the levels of serum and
secretory
IgA
that results from the inability of mature B cells to transform into
IgA
secreting plasma cells
Usually there are
normal level of other
isotypes
Persons with this disease tend to be affected with:
Chronic upper respiratory infections
Chronic GI infections
Increased incidence of allergic diseases such as asthma
Treatment : antibiotics, not
immunoglobulins
Slide24Isotype
Switching Dose Not Occur..
Hyper-
Igm
(
HIgM
)
Defect in gene encoding
the CD40
Ligand
on T cell which is important in the
costimulatory
signal required for class switching from
IgM
to
IgG
,
IgA
and
IgE
(The B-cell response to T-independent antigens only)
Symptoms : High serum titers of
IgM
without other
isotypes
, normal B & T cell
Although this form of immunodeficiency results in alterations in antibody production and presents with symptoms similar to HIM variants, it is classified as a CID
Increased susceptibility to
extracellular
bacteria & opportunists
Treatment : antibiotics and
gammaglobulins
CD40 ligand
T h
B
Cytokines - IL-4, 5, 6
CD40 ligand
Slide26Disease
Molecular defect
Symptoms/signs
Treatment
Bruton X-linked hypogammagloulinemia
Def of tyrosine kinase so blocks B-cell maturation
1.
Low Ig of all classes.
2.
No circulating B cell.
3.
B-cell maturation stopped at pre-B stage.
4.
Normal CMI.
1.Monthly gammaglobulin replacement.
2.Antibiotic.
X-linked hyper-IgM syndrome
Def of CD40L on activated T cell
1.
Higher serum titer of IgM only.
2.
Normal B & T cell number.
3.
Susceptibility to EC bacteria & opportunists.
Antibiotic & gammaglobulin
.
Examples for humoral immunity defects.
Slide27Disease
Molecular defect
Symptoms/signs
Treatment
Selective IgA deficiency
Deficiency of IgA
Repeated
sinopulmonary
& GIT infections.
Antibiotic, not
Ig
.
Common variable immunodef
Unknown
1.
onset in late teens.
2.
B cell present in peripheral blood.
3.
Ig level decrease with time.
4.
increase autoimmunity &
atopy
Antibiotics
Slide28T- Cell Deficiency
Caused by problem with T lymphocytes (both CD4
+
helper cells and CD8
+
cytotoxic
killer cells)
Patient’s have
more severe
symptoms than with
humoral
immunodeficiency
Slide29Defect in T-Cell
Combined partial B & T cell defect
Defect in cells that are critical to the development or activation of T cell (APC)
Reduced MHC I molecules
Decrease No. of functional CD8+ & NK
Reduced MHC II molecules
Decrease No. of functional CD4+
Defects in
thymic
development (abnormal embryonic changes)
Prevent
thymic
education of T cell
Slide30Defect in T cell development
Progenitor
Progenitor
Slide31Defects in
thymic
development
DiGeorge's
syndrome:
It is the most understood T-cell
immunodeficienc
Also known as
congenital
thymic
aplasia
/
hypoplasia
Associated with
hypoparathyroidism
, congenital heart disease, fish shaped mouth.
Defects results from
abnormal development of fetus during 6th-10th week
of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed
Slide32MHC DEFICIENCY
class II deficiency
(Bare lymphocytes syndrome II):
Due to
defect in the MHC class II
transactivator
protein gene, which results in a lack of class-II MHC molecule on
APC.
Patients have
fewer CD4
cells , immunoglobulin levels decreased owing to defective T-cell help
Increased susceptibility to infection
Slide33MHC DEFICIENCY
class I deficiency
(
Bare lymphocytes syndrome I
or
TAP- 1 or 2 deficiency
):
There are also individuals who have a defect in their
transport associated protein (TAP)
gene and hence do not express the class-I MHC molecules and consequently are
deficient in CD8+ T cells
, CD4+ normal
recurrent viral infection , normal DTH, normal
Ab
production
Slide34Combiend
partial B- and T-cell deficiency
Ataxia-telangiectasia:
Defect in kinase involved in cell cycle
Associated with a lack of coordination of movement (
ataxis
) and dilation of small blood vessels of the facial area (
telangiectasis
).
T-cells and their functions are reduced to various degrees.
B cell numbers and IgM concentrations are normal to low.
Slide35Defects in Lymphoid Lineage
Progenitor
Progenitor
Slide36Complete functional B- and T-cell deficiency
Severe Combined
Immunodeficency
(SCID)
In about 50% of SCID patients the immunodeficiency is
x-linked
whereas in the other half the deficiency is
autosomal
.
They are both characterized by an
absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes
.
Patients with SCID are susceptible to a variety of bacterial, viral,
mycotic
and protozoan infections.
Slide37Severe Combined
Immunodeficency
(SCID)
The
x
-linked SCID is due to a defect in
gamma-chain of IL-2
also shared by IL-4, -7, -11 and 15, all involved in lymphocyte proliferation and/or differentiation.(more common in male)
the
autosomal
SCIDs arise primarily from defects in
adenosine
deaminase
(ADA)
or
purine
nucleoside
phosphorylase
(PNP)
genes which results is accumulation of
dATP
or
dGTP
, respectively, and cause toxicity to lymphoid stem cells and apoptosis(T,B &NK)
Slide38Severe Combined
Immunodeficency
(SCID)
3.
Mutations in the recombinase activating genes
RAG-1 & RAG-2 gene deficiency
which are absolutely required for cleaving dsDNA
befor
recombination of DNA to form the Ig genes encoding T cell receptors leading to undeveloped B & T cell
4.
&
genes encoding proteins involved in the DNA excision-repair pathways employed during gene rearrangement (e.g.,
Artemis) can
also lead to SCID
Slide395.
In
reticular
dysgenesis
(RD), the initial stages of hematopoietic cell
development are blocked by defects in the
adenylate
kinase
2 gene (AK2), favoring apoptosis of myeloid and lymphoid
precursors and resulting in severe reductions in circulating leukocytes
Slide40Slide41screening test for SCID develop the standard blood samples collected from neonates via heel or finger pricks
Rapid polymerase chain reaction (PCR)-based assay looks for evidence of gene recombination as in excised DNA from the TCR or BCR locus, called T-cell receptor excision circles (TRECs) and -deleting recombination excision circles (KRECs).
In 2010, recommendations to screen every newborn for SCID were approved.
Slide42Disease
Defect
Clinical manifestation
DiGeorge syndrome
Thymic
aplasia
Depression of T cell number with absence of responses.
MHC class I deficiency
Failure of TAP 1 molecule to transport peptide to endoplasmic reticulum
1.
CD8+ T cell def.
2.
CD4+ T cell normal.
3.
Recurrent viral infection.
4.
Normal Ab formation.
MHC class II def(Bare lymphocyte syndrome)
Defects in transcription factors.
1.
def of CD4+ T cell.
2.
Hypogammagloulinemia.
3.
Clinically as SCID.
B and T-cell deficiency
divided into these categories:
A
. Selective T-cell deficiency
:
Slide43B. Combined partial B and T-cell deficiency:
Ataxia telangiectasia
Defect in kinase involved in the cell cycle.
1. gait abnormality.
2. Telangectasia (capillary distortion in the eye).
3.def of IgA & IgE production.
C.
Complete functional B and T cell deficiency:
Sever combined ID(SCID).
Defects in common γ chain of IL-2 receptor.
1. Opportunistic (fungal) infection.
2. Low level of circulating lymphocyte.
Slide44Disorders of complement system
:
Complement abnormalities also lead to increased susceptibility to infections.
There are genetic deficiencies of various components of complement system, which lead to increased infections.
The most serious among these is the C3 deficiency which may arise from low C3 synthesis or deficiency in factor I or factor H.
Slide45Disorders of complement system
Due to
Classical pathway
Both pathway
Deficiencies in complement regulatory proteins
Slide46Defect in classical pathway
Deficiencies of the classical pathway C1q, C1r, C1s, C4, or C2
Result in a propensity to develop immune complex diseases such as SLE because it required for the dissolution of immune complexes
Increasing the risk of immune complex diseases SLE and increased infections with
pyogenic
bacteria
Slide47Deficiency in both pathways
Deficiency in C3 result in recurrent bacterial infection (
pyogenic
) indicating the importing role of C3 in
opsonization
of
pyogenic
bacteria
Deficiency of the terminal components C5-C8 result in remarkable susceptibility to infection with meningococcal &
gonoccocal
infections
Slide48Deficiencies in complement regulatory proteins
The most important deficiency of the complement system is C1 inhibitor which is responsible for dissociation of activated C1 by binding to C1r2 C1s2
Deficiency result in
Hereditary
angioedema
(HAE)
Patients have recurrent
Episodes of swelling at
mucosal surfaces
4. Defects of complement.
Deficiencies of complement or its regulation as in these cases:
Components
Deficiency
Signs/diagnosis
Classic pathway
C1q,C1r,C1s,C4,C2
1.
Marked increase in immune complex disease.
2.
Increased infection with pyogenic bacteria.
Both pathways
C3
1.
Recurrent bacterial infection.
2.
Immune complex disease.
C5,C6,C7,C8
Recurrent meningococcal & gonococcal infections.
Def of regulatory proteins.
C1-INH (hereditary angioedema)
1.
Overuse of C1,C4 or C2.
2.
Edema at mucosal surfaces.
Slide50Type Of Infection Helps Predict The Type Of Immunodeficiency
B lymphocyte -
pyogenic
bacteria - lungs
T lymphocyte - viruses, fungi,
mycobacteria
Complement -
meningococcus
- CNS
Phagocyte - staphylococcus - skin
Slide51Slide52Immunodefi
ciency
That Disrupts Immune Regulation Can Manifest as Autoimmunity
immune system must learn to recognize
selfMHC
proteins and to be proactive in suppressing reactions to self antigens in the host by the induction of tolerance in the thymus and by the surveillance activities of regulatory T cells.
Gene defect caused by inborn immunodeficiencies, actually manifest as immune overactivity, or autoimmunity
Slide53Autoimmune
Polyendocrinopathy
and
Ectodermal
Dystrophy
(APECED)
A defect in the
autoimmune regulatory gene
AIRE
protein
is expressed in
medullary
epithelial cells of the thymus, where it acts as a transcription factor to control expression of a whole host of tissue-restricted antigens.
Facilitates the negative selection of potentially
autoreactive
T cells before they can exit into the circulation.
organ-specific autoimmunity.
Slide54Immune
Dysregulation,Polyendocrinopathy
,
Enteropathy
, X-linked
(IPEX
) Syndrome
Patients with
(IPEX)
syndrome have inherited a mutated
FoxP3 gene and lack
expression of this protein, leading to a near absence of TREG cells.
Without these regulatory cells in the periphery,
autoreactive
T cells that have escaped central tolerance in the thymus go unchecked, leading to systemic autoimmune disease.
Slide55Progenitor
Progenitor
Reticular
Dysgenesis
SCID
DiGeorge Syndrome (Autosomal dominant)
Common Variable
Hypo
g
globulinemia/
X-linked hyperIgM
Syndrome/Selective
Ig deficiency
xLA
Congenital
Agranulocytosis
Chronic Granulomatous Disease
Auto. rec./X-linked)
Overview of Primary Immunodeficiencies
Slide56Refferences
:
Immunology ,
Kuby
, seventh edition 2013
Immunology ,
Kuby
, eighth edition 2019
Cellular and Molecular Immunology, Abul K. Abbas, 8
th
edition.