Pathophysiology of Immunodeficiency Diseases Host Defense Mechanisms Skin and mucosal barriers Humoral immunity (B cells, plasma cells, Ab) Cell-mediated.

Pathophysiology of Immunodeficiency Diseases

Host Defense Mechanisms

• Skin and mucosal barriers• Humoral immunity (B cells, plasma cells, Ab)• Cell-mediated immunity (T cells)• Phagocytosis• Complement

Overview of Immunodeficiency

Disorders.

The defect might beIn the level of

stem cell or

in any otherlevel of tree

Introduction.

• Immunodeficiency diseases are :A diverse spectrum of illnesses due to various abnormalities of the immune system

• Prevalence : Primary (congenital) 1 : 10,000 to 1 : 200,000

present at birth .

Secondary (acquired) is more common .

Origins of Immunodeficiencyo Primary or Congenital

Inherited genetic defects in immune cell development or function, or inherited deficiency in a particular immune component

o Secondary or acquiredA loss of previously functional immunity due to infection, toxicity, radiation, splenectomy, aging, malnutrition, etc.

Primary or acquired. can affect.

Natural immunity (non-specific body defenses).

Acquired immunity. (specific body defenses).

Phagocytic cells.

Complement proteins.

T-cells. B-cells.

Immunodeficiency / Immunocompromised States

Primary– Intrinsic abnormality of one or more components of the

Immune System• >150 Conditions Characterised• Individually, uncommon, but important to recognise• Range from global, overwhelming immune failure ( SCID) to subtle

defects in individual components of function

• 1/ 10,000 live births

Suspecting Immunodeficiency• Look for infections that are:

Frequent

Recurrent/chronic

Unusual organisms: aspergillous, nocardia

Organisms that respond poorly to therapy

Unusual site: liver abcess, brain abcess

Severity of infection

8 or more ear infectionswithin 1 year

2 or more serious sinus infectionswithin 1 year

2 or more months on antibiotics without resolution

2 or more pneumoniaswithin 1 year

Failure to gain weight or grownormally

Persistent candidiasis after the age of 1 year

Need for I.V. antibiotic to clear infections

2 or more deep-seatedinfections

A family history of Primary Immunodeficiency

Recurrent, deep skin or organ abscesses

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The Ten Warning Signs of Primary Immunodeficiency

Classification of Primary Immunodeficiency

1. Antibody deficiencies

2. Cellular deficiencies

3. Phagocytic disorders

4. Complement deficiencies

5. Combined Immunodeficiencies

HUMORAL Immunodeficiencies(B-cell defects)

Common variable immunodeficiency (CVID) X-linked agammaglobulinemia (XLA) Selective IgA deficiency (SIgAd) Selective IgG subclass deficiency (SIgGsd) Hyper IgM syndrome (HIgM) Transient hypogammaglobulinemia of Infancy (THI) Functional antibody deficiency

Antibody deficiencies include:

Early B-cell differentiation .

Lesions can occur at any site in the pathway of B-cell development.B-cell defect could be in any level in the pathway

B-cell Defect

Onset after maternal antibodies diminishUsually after 5-7 m/o, later childhood to

adulthoodBacteria: pneumococci, staphylococci,

Hemophilus, campylobacter, mycoplasmaVirus: entovirusRecurrent sinopulmonary infections, chronic GI

symptoms, malabsorptions, arthritis, entroviral meningoencephalitis

X-linked agammaglobulinaemia(bruton)

In X-LA early maturation of B cells fails

Affect malesFew or no B cells in bloodVery small lymph nodes and tonsilsNo IgRecurrent pyogenic infection

Serum IgA level < 10 mg/dl Prevalence :1:700 , the most common PID

Most are asymptomatic , but have Increased rate of respiratory tract infection (R.T.I )

Some have recurrent G.I.T. , Urogenital tract Symptoms

Because of lack of secretion of IgA on the mucous membrane of GIT and respiratory tract

Increased incidence of allergic and autoimmune diseases

Anti - convlusant drugs (phenytoin) may cause secondary deficiency

IgA deficiency

2- IgA and IgG subclass defeciency

About 20% lack IgG2and IgG4Susceptible to pyogenic infectionResult from failure in terminal

differentiation of B cells

3- Immunodfeiciency with increased IgM (HIgM)Low or absent levels of IgA, IgG , IgE Production of large amount of IgM

>200mg/dl of polyclonal IgMSusceptible to pyogenic infection Due to inability of B cells to isotype

switchingThey have B cell

4- Common Variable Immunodeficiency (CVID)

There are defect in T cell signaling to B cellsAcquired agammaglobulinemia in the 2nd or

3rd decade of lifePyogenic infection80% of patients have B cells that are not

functioningB cells are not defective but donot

differentiate into immunoglobulin producing cell and fail to receive signaling from T lymphocytes

Risk of autoimmune disease and malignancy

5- Hypogamaglobulinaemia of infancy

Due to delay in in IgG synthesis approximately up to 36 months

In normal infants synthesis begins at 3 months

Normal B lymphocytesProbably lack help of T lymphocytes

Immunoglobulin Levels vs. Age

Cellular Immunodeficiencies

Combined immunodeficiency (CID) Severe combined immunodeficiency (SCID) Ataxia-Telangiectasia syndrome (AT) Wiskott-Aldrich syndrome (WAS) DiGeorge syndrome Chronic mucocutaneous candidiasis (CMCC)

Cellular deficiencies include:

DiGeorge's syndrome

It 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

Combined T & B Immunodeficiencies

SEVERE COMBINED IMMUNODEFICENCY

In about 50% of SCID patients the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal.

Early onset( 2-6 m/o) Lymphopenia((< 2500 in infants) They are both characterized by an absence of T cell and B

cell immunity and absence (or very low numbers) of circulating T .

Very small thymus, no lymph node , no tonsil Patients with SCID are susceptible to a variety of bacterial,

viral, mycotic and protozoan infections.

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.

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

Ataxia-telangiectasia

A complex of immunologic, neurologic, endocrinologic,

hepatic and cutaneous abnormalities ataxia(10-12y/o) ,telangiectasis (3-6 y/o) Mutation in ATM gene T-cells and their functions are reduced to various

degrees. B cell numbers are normal to low. Low levels of IgA, IgE, high level of IgM There is a high incidence of malignancy, particularly

lymphoreicular & adenocarcinoma

Wiskott-Aldrich syndrome(immunodeficiency with thrombocytopenia and eczema)

X-linked xp11.22-11.23WASP ; assemby of actin filaments required for

microvesicle formation downstream of protein kinase C and tyrosine kinase signaling

Low plaletlet, small size platelet

Associated with normal T cell numbers with reduced functions, which get progressively worse.

IgM concentrations are reduced but IgG levels are normal

Both IgA and IgE levels are elevated.

Boys with this syndrome develop severe eczema,bleeding tendency

They respond poorly to polysaccharide antigens and are prone to pyogenic infection.

Defects of the phagocytic system

• Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a variety of infections.

• Bacteria,fungal infection• Skin and mucus membrane

Cyclic neutropenia

Autosomal dominantMutation in ELA2(neutrophil elastase gene2)It is marked by low numbers of circulating

neutrophil approximately every three weeks. The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production.

Tx: r-GCSF ( granulocyte stimulating factor)

Severe congenital Neutropenia(Kostman)

Arrest in promyelocyte stageNeutrophil count< 200Mutation ELA2 or HAX1, autosomal recessive

or dominantSevere infections20% prone to AMLTx: r-GCSF

Shwachman Diamond Syndrome

Mutation in SBDS geneDiarrhea, FTT, malabsorption till 4 m/oEczema, recurrent infectionsNeutrophil count< 1000, pancytopeniaRisk of AML

Chronic granulomatous disease (CGD)

• Defect in intra cellular killing• Normal chemotaxis, ingestion• Normal neutrophil count• x-linked (65%)& autosomal recessive• CGD is characterized lymphadenopathy, hepato-

splenomegaly and chronic draining lymph nodes. • In majority of patients with CGD, the deficiency is

due to a defect in NADPH oxidase that participate in phagocytic respiratory burst.

• Infection with catalase positive organism: e coli, staph areus , fungal , nocardia, serratia

Leukocyte Adhesion DeficiencyLAD1, LAD2,LAD3

Autosomal recessive Defect in chemotaxis These molecules are involved in diapedesis and

hence defective neutrophils cannot respond effectively to chemotactic signals.

Neutrophilia >12,000 , with infection >100,000 Delayed umblical cord separation > 2 wk They don't have sign of inflammation such as

swelling, warmth or pus formation

Chediak-Higashi syndrome(granule sorting disorder)

Mutation in lyst geneGiant granule in cytoplasm of neutrophilsRespiratory burst is normal. Associated with NK cell defect, platelet and

neurological disorders

• Albinism(oculocutaneous)• Repeated infections• Mild bleeding tendency• Peripheral neuropathy• Prone to hemophagocytic syndrome

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. 

Defect in classic pathway; AUTOIMMUNE DISEASECongenital deficiency of C5, 6, 7, 8: > 50%

MENINGOCOCCAL or GONOCOCCAL INFECTION( neisseria)

Hyper IgE (Job) syndrome

Autosomal dominantSymptoms/signs

Coarse facial features/skeletal abnormalitiesRecurrent staph infections

Impetigo (resistant)Pneumonia with pneumatocele formation Elevated IgE, Eosinophilia, Eczema

PID - treatments

• Immunoglobulin replacement• Bone Marrow Transplantation• Gene-based therapies• Antimicrobial management and prophylaxis• Nutritional Support• Patient Support Groups