IMMUNE DEFICIENCY Dr. Refif Al- - PowerPoint Presentation

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IMMUNE DEFICIENCY

Dr. Refif Al-

shawk

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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

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Immune deficiency occur in two different ways

Primary I.D.

-

usually genetic, congenital

Secondary I.D.

-

Acquired (infection ,therapeutic treatments, cancer & malnutrition)

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Mechanisms of Immunodeficiency

Loss or reduction of:

Cell type

Cell numbers

Cell function

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Loss of Cell Function

Receptors

Cell signaling

Cytokine production

Ig

production

Co-stimulation impairment

Intracellular killing

Extravasation

impairment

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Characteristics 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

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Hematopoiesis

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Primary 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

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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)

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Defects in Myeloid Lineage

Progenitor

Progenitor

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Chronic

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

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Chediak

- 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

)

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Leukocyte 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

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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)

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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

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Defects 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

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Defects in B cell development

Progenitor

Progenitor

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Early 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

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Otitis

media

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Terminal 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

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Isotype

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

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CD40 ligand

T h

B

Cytokines - IL-4, 5, 6

CD40 ligand

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Disease

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.

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Disease

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

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T- 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

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Defect 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

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Defect in T cell development

Progenitor

Progenitor

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Defects 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

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MHC 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

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MHC 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

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Combiend

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.

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Defects in Lymphoid Lineage

Progenitor

Progenitor

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Complete 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.

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Severe 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)

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Severe 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

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5.

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

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screening 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.

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Disease

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

:

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B. 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.

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Disorders 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. 

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Disorders of complement system

Due to

Classical pathway

Both pathway

Deficiencies in complement regulatory proteins

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Defect 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

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Deficiency 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

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Deficiencies 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

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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.

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Type Of Infection Helps Predict The Type Of Immunodeficiency

B lymphocyte -

pyogenic

bacteria - lungs

T lymphocyte - viruses, fungi,

mycobacteria

Complement -

meningococcus

- CNS

Phagocyte - staphylococcus - skin

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Immunodefi

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

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Autoimmune

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.

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Immune

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.

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Progenitor

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

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Refferences

:

Immunology ,

Kuby

, seventh edition 2013

Immunology ,

Kuby

, eighth edition 2019

Cellular and Molecular Immunology, Abul K. Abbas, 8

th

edition.