الرحمن الله الرحمن بسم الله بسمالرحيمالرحيمCOMBINED COMBINED

IMMUNODEFICIENCYIMMUNODEFICIENCY

Dr Tai Al AkawyPediatrician and NeonatologistAlexandria University Children’s Hospital

Immunodeficiency Immunodeficiency disordersdisorders

DefinitionDefinition

Immunodeficiency- an abnormality of the Immunodeficiency- an abnormality of the immune system that renders a person immune system that renders a person susceptible to diseases that is prevented susceptible to diseases that is prevented by a normal functioning immune systemby a normal functioning immune system

Classification Classification Primary or congenital immunodeficienciesPrimary or congenital immunodeficiencies

Present at birthPresent at birth Result from genetic abnormalities in one or more Result from genetic abnormalities in one or more

components of the immune systemcomponents of the immune system

Secondary or acquired immunodeficienciesSecondary or acquired immunodeficiencies Later in lifeLater in life Result from infections, malnutrition, or drugsResult from infections, malnutrition, or drugs

Classified asClassified as

SECONDARY IMMUNODEFECIENCY.DRUGS.INFECTIONS

HUMORAL IMMUNITY

CELL MEDIATED IMMUNITY

PHAGOCYTOSIS

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Four Major Host Defense Four Major Host Defense DeficienciesDeficiencies

2.2. T-cell or combined T-cell or combined immunodeficienciesimmunodeficiencies

3.3. Phagocyte disordersPhagocyte disorders

4.4. Complement disordersComplement disorders

1.1. B-cell (humoral) immunodeficienciesB-cell (humoral) immunodeficiencies

Primary Primary immunodeficienciesimmunodeficiencies

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Combined Combined ImmunodeficienciesImmunodeficienciesare immunodeficiency disorders that are immunodeficiency disorders that involve multiple components of involve multiple components of the immune system, including the immune system, including both humoral immunity and cell-both humoral immunity and cell-mediated immunitymediated immunity

Functional Classification T Functional Classification T cells/combined Idcells/combined Id..

SCIDSCID ( (bubble boy diseasebubble boy disease) ) a genetic disease that results when one of a genetic disease that results when one of

the thirteen genes involved in a molecular the thirteen genes involved in a molecular mechanism known as mechanism known as somatic re-somatic re-combinationcombination is mutated. is mutated.

Somatic recombination is responsible for Somatic recombination is responsible for giving rise to giving rise to variable B and T cell variable B and T cell receptors receptors

It's classified to many types It's classified to many types according to the mutated gene. according to the mutated gene.

Congenital immunodeficiencies that affect both Congenital immunodeficiencies that affect both humoral and cell-mediated immunityhumoral and cell-mediated immunity

characterized by deficiencies of both characterized by deficiencies of both B and T B and T cells or only of T cellscells or only of T cells; ;

in the latter cases, the defect in humoral in the latter cases, the defect in humoral immunity is immunity is due to the absence of T cell helpdue to the absence of T cell help..

Children with SCID usually have infections Children with SCID usually have infections during the first year of life.during the first year of life.

Severe Combined Severe Combined Immunodeficiency Syndromes Immunodeficiency Syndromes

(SCID)(SCID)

IntroductionIntroduction Severe combined Severe combined

immunodeficiency immunodeficiency (SCID) is a group of (SCID) is a group of fatal disorder that fatal disorder that results in little or no results in little or no immune response. The immune response. The disease is also called disease is also called ‘bubble boy’ disease. ‘bubble boy’ disease.

Bubble Boy DiseaseBubble Boy Disease SCID is often called “bubble boy disease”.SCID is often called “bubble boy disease”. SCID became widely known during the 1970′s and 80′s, SCID became widely known during the 1970′s and 80′s,

when the world learned of when the world learned of David VetterDavid Vetter, a boy with X-, a boy with X-linked SCID, who lived for 12 years in a plastic, germ-linked SCID, who lived for 12 years in a plastic, germ-free bubble.free bubble.

TYPES

TYPESTYPES

1.1. X-LINKED SEVERE COMBINED X-LINKED SEVERE COMBINED IMMUNODEFICIENCYIMMUNODEFICIENCY

2.2. ADENOSINE DEAMINASE DEFICIENCYADENOSINE DEAMINASE DEFICIENCY3.3. PURINE NUCLEOSIDE PHOSPHORYLASE PURINE NUCLEOSIDE PHOSPHORYLASE

DEFICIENCYDEFICIENCY4.4. RETICULAR DYSGENESISRETICULAR DYSGENESIS5.5. OMENN SYNDROMEOMENN SYNDROME6.6. BARE LYMPHOCYTE SYNDROMEBARE LYMPHOCYTE SYNDROME7.7. JANUS KINASE-3 (JAK3)JANUS KINASE-3 (JAK3)8.8. ARTEMIS/DCLRE1CARTEMIS/DCLRE1C

X-Linked SCID: Common Cytokine X-Linked SCID: Common Cytokine Receptor Gamma Chain (gc) DeficiencyReceptor Gamma Chain (gc) Deficiency

Most common form of SCID (40%)Most common form of SCID (40%)

Responsible gene: Responsible gene: γγcc– the common subunit of – the common subunit of receptors for receptors for IL-2, IL-4, IL-7, IL-9, and IL-15IL-2, IL-4, IL-7, IL-9, and IL-15

Very low T cells and NK cellsVery low T cells and NK cells with low to normal with low to normal numbers of B cellsnumbers of B cells

X-SCID X-SCID This type of SCID is caused by a mutation This type of SCID is caused by a mutation

occurring in the occurring in the xq13.1 locus xq13.1 locus of the X-of the X-chromosome.chromosome.

Deficiency of the Common Gamma Chain of the T-Cell Deficiency of the Common Gamma Chain of the T-Cell Receptor (X-SCID) Receptor (X-SCID)

Adenosine deaminase (ADA) Adenosine deaminase (ADA)

Adenosine Adenosine deaminase is the deaminase is the enzyme that is enzyme that is affected during affected during ADA deficiency. ADA deficiency.

DeoxyadenosineDeoxyadenosine is accumulated as is accumulated as the result of ADAthe result of ADA

def.def.

Adenosine Deaminase DeficiencyAdenosine Deaminase Deficiency

Babies with this type of SCID have Babies with this type of SCID have the lowest the lowest total lymphocyte counts of alltotal lymphocyte counts of all, and , and T, B and T, B and NK-lymphocyte counts are all very lowNK-lymphocyte counts are all very low. . This form of SCID is inherited as This form of SCID is inherited as an an autosomal recessive autosomal recessive trait. trait.

Lack of the ADA enzyme also leads to Lack of the ADA enzyme also leads to neurological neurological problemsproblems such as such as -cognitive impairment-cognitive impairment -hearing and visual impairment-hearing and visual impairment -low muscle tone and movement disorders. -low muscle tone and movement disorders.

The neurological problems are The neurological problems are notnot fully curable by fully curable by bone marrow transplantationbone marrow transplantationGene was identified in 1992Gene was identified in 1992

Purine nucleoside phosphorylase Purine nucleoside phosphorylase (PNP) deficiency (PNP) deficiency

PNP is a key enzyme in the purine PNP is a key enzyme in the purine salvage pathwaysalvage pathway

PNP deficiency is a combined PNP deficiency is a combined immunodeficiency caused by mutations in immunodeficiency caused by mutations in the enzyme PNP the enzyme PNP

and subsequent and subsequent accumulation of purine accumulation of purine metabolitesmetabolites such as deoxyguanosine such as deoxyguanosine

Purine nucleoside phosphorylase Purine nucleoside phosphorylase (PNP) deficiency (PNP) deficiency

Patients typically present with Patients typically present with recurrent recurrent infectionsinfections, , autoimmunityautoimmunity and and ataxiaataxia. .

Presentation may be delayed beyond 1–2 Presentation may be delayed beyond 1–2 years of lifeyears of life

An autosomal recessive An autosomal recessive traittrait PNP deficiency is PNP deficiency is a rare a rare disease with an disease with an

estimated frequency of 4% among patients estimated frequency of 4% among patients with SCID with SCID

Severe Combined ImmunodeficiencySevere Combined Immunodeficiency

Presentation usually< 6 mo agePresentation usually< 6 mo age Opportunistis infections and recurrent Opportunistis infections and recurrent

pyogenic infections, chronic pyogenic infections, chronic diarrhea , FTT, eczemadiarrhea , FTT, eczema Male: female 4:1 (most common Male: female 4:1 (most common form is X-linked)form is X-linked) Often fatal befor 1 year of age if untreatedOften fatal befor 1 year of age if untreated

Other Forms of severe combinedOther Forms of severe combined Immunodeficiency Immunodeficiency

Deficiency of the Alpha Chain of the IL-7 ReceptorDeficiency of the Alpha Chain of the IL-7 Receptor

This form of SCID is due to mutations in a gene that encodes This form of SCID is due to mutations in a gene that encodes the alpha chain of the IL-7 receptor (IL-7Rα).the alpha chain of the IL-7 receptor (IL-7Rα).

Infants with this type Infants with this type have B- cells and NK-cellshave B- cells and NK-cells, but , but no T-no T-cells.cells.

However, the B-cells do not work because of the lack of T-However, the B-cells do not work because of the lack of T-cells.cells. IL-7Rα deficiency is IL-7Rα deficiency is the third most common the third most common cause of SCID cause of SCID accounting for 11% of SCID cases.accounting for 11% of SCID cases.

It is inherited It is inherited as an autosomal recessive traitas an autosomal recessive trait..

Deficiency of Janus Kinase 3 Deficiency of Janus Kinase 3 It is a defect in the cytokine receptors and their signalingIt is a defect in the cytokine receptors and their signaling..

Janus kinase 3, a tyrosine kinase that belongs to the Janus family.Janus kinase 3, a tyrosine kinase that belongs to the Janus family.

JAK3 functions in JAK3 functions in signal transduction signal transduction and interacts with members of and interacts with members of the STAT family. the STAT family.

This enzyme is This enzyme is necessary for function γcnecessary for function γc..

Thus, when T, B and NK-lymphocyte counts are done, Thus, when T, B and NK-lymphocyte counts are done, they are they are T-, B+, NK-T-, B+, NK-. . Since this form of SCID is inherited as Since this form of SCID is inherited as an autosomal recessive an autosomal recessive trait trait both boys and girls can be affected.both boys and girls can be affected.

T- , B-, NK+T- , B-, NK+ 10% of SCID genes identified in 198910% of SCID genes identified in 1989 RAG1 and RAG2 form a hetero-dimer that RAG1 and RAG2 form a hetero-dimer that

is required to is required to initiate VDJ recombination initiate VDJ recombination in in order to generate order to generate diverse repertoires of T diverse repertoires of T and B cell receptors and B cell receptors capable of capable of recognizing a wide range of pathogen recognizing a wide range of pathogen epitopesepitopes

RAG1 and RAG2 Deficiency- ARRAG1 and RAG2 Deficiency- AR

SCIDS DefectSCIDS Defect

RAG1 and RAG2 Deficiency- ARRAG1 and RAG2 Deficiency- AR

Moderate lymphopenia (mean ALC 1000)Moderate lymphopenia (mean ALC 1000) Amino acid substitutions can cause Amino acid substitutions can cause

Omenn Syndrome Omenn Syndrome ((SCID with hyper-SCID with hyper-eosinophiliaeosinophilia))

Omenn syndrome is the type results when Omenn syndrome is the type results when RAG coding gene is mutated RAG coding gene is mutated

Omenn syndromeOmenn syndrome poorly functional Th2 cells produce poorly functional Th2 cells produce

elevated levels of IL-4 and IL-5 whichelevated levels of IL-4 and IL-5 which lead to lead to hypereosinophilia hypereosinophilia and despite the and despite the

absence of B cells, increased serum levels absence of B cells, increased serum levels of of IgEIgE..

Omenn syndromeOmenn syndrome also characterized by also characterized by lymphadenopathy lymphadenopathy

and and hepatosplenomegalyhepatosplenomegaly which are which are problems unusual in other types of SCID.problems unusual in other types of SCID.

Patients also suffer from alopecia and an Patients also suffer from alopecia and an exudative erythrodermia exudative erythrodermia that is associated that is associated with episodes of with episodes of Staphylococcus aureus Staphylococcus aureus sepsis.sepsis.

Bare-lymphocyte syndromeBare-lymphocyte syndrome

Condition caused by mutations in certain genes of the Condition caused by mutations in certain genes of the major histocompatibility complex.major histocompatibility complex.

Without these molecules, the patient’s lymphocytes Without these molecules, the patient’s lymphocytes cannot cannot participate in cellular interactions with T helper cellsparticipate in cellular interactions with T helper cells. .

This includes defective interaction between a 5’ promoter This includes defective interaction between a 5’ promoter sequence of the gene for sequence of the gene for the class II MHC molecule the class II MHC molecule and a and a DNA-binding protein necessary for gene transcriptionDNA-binding protein necessary for gene transcription..

Bare-lymphocyte syndromeBare-lymphocyte syndrome TAP complex, the peptide transporter TAP complex, the peptide transporter

associated with antigen presentation associated with antigen presentation causing (causing (TAP deficiency syndromeTAP deficiency syndrome))..

Bare lymphocyte syndrome (BLS) is Bare lymphocyte syndrome (BLS) is characterized by a severe down-regulation characterized by a severe down-regulation of HLA class I and/or class II molecules of HLA class I and/or class II molecules

In type 1 BLS the defect is confined to In type 1 BLS the defect is confined to HLA class I molecules, HLA class I molecules,

while in type 2 BLS HLA class II molecules while in type 2 BLS HLA class II molecules are down-regulated . are down-regulated .

Characterization of 22 patients with type 1 Characterization of 22 patients with type 1 BLS over the last 22 years has revealed BLS over the last 22 years has revealed the existence of several clinically and the existence of several clinically and immunologically distinct disease subsets.immunologically distinct disease subsets.

Reticular dysgenesis

•Is a rare genetic disorder of the bone marrow resulting in complete absence of granulocytes and decreased number or abnormal lymphocytes.

• Production of red blood cells (erythrocytes) and megakaryocytes (platelet precursors) is not affected.

•There is also poor development of the secondary lymphoid organ.

•The cause of reticular dysgenesis is the inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 mutation

Common Features of Severe Combined Common Features of Severe Combined Immunodeficiency (SCID)Immunodeficiency (SCID)

Failure to thriveFailure to thrive Onset of infections in the neonatal Onset of infections in the neonatal

periodperiod Opportunistic infectionsOpportunistic infections Chronic or recurrent thrushChronic or recurrent thrush Chronic rashesChronic rashes Chronic or recurrent diarrheaChronic or recurrent diarrhea Paucity of lymphoid tissuePaucity of lymphoid tissue

Clinical Presentation of Severe Clinical Presentation of Severe Combined Immune DeficiencyCombined Immune Deficiency

Children with SCID may develop infections caused by Children with SCID may develop infections caused by organisms or organisms or vaccines. vaccines.

Among the most dangerous is an organism called Among the most dangerous is an organism called Pneumocystis Pneumocystis jirovecijiroveci, which can cause a rapidly fatal pneumonia (PCP) if not , which can cause a rapidly fatal pneumonia (PCP) if not diagnosed and treated promptly.diagnosed and treated promptly.

Another dangerous organism is the chicken pox virus (Another dangerous organism is the chicken pox virus (varicellavaricella).).

In the patient with SCID, chicken pox can be fatal because it does In the patient with SCID, chicken pox can be fatal because it does not resolve and can progress to cause infection in the lungs, liver not resolve and can progress to cause infection in the lungs, liver and brain.and brain.

Cytomegalovirus (Cytomegalovirus (CMVCMV), may cause fatal pneumonia in patients ), may cause fatal pneumonia in patients

with SCIDwith SCID

• Other dangerous viruses for patients with SCID are the cold sore virus (Herpes simplex), adenovirus, para influenza 3, Epstein-Barr virus (EBV, the infectious mononucleosis virus), polioviruses, measles virus (rubella) and rotavirus.

• Fungal infections in patients with SCID may be very difficult to treats such as oral thrush.

• Candida pneumonia, abscesses, esophageal infection or even meningitis may develop in patients with SCID.

• Persistent diarrhea, resulting in growth failure or malabsorption, is a common problem in children with SCID.

• Patients with SCID may also have a rash that is mistakenly diagnosed as eczema, but is actually caused by a reaction of the mother’s T-cells (that entered the SCID baby’s circulation before birth) against the baby’s tissues. This reaction is called graft-versus-host disease (GVHD).

combinedcombined ImmunodeficiencyImmunodeficiency

Results from a mutation on chromosome 11Results from a mutation on chromosome 11 Condition consists of Condition consists of worsening ataxia worsening ataxia (lack of (lack of

coordination) and coordination) and telangiectasiatelangiectasia (dilated capillaries (dilated capillaries and arterioles) on the skin and conjunctiva.and arterioles) on the skin and conjunctiva.

Children have reduced levels of Children have reduced levels of IgA, IgE, and IgGIgA, IgE, and IgG, , and and decreased ratio decreased ratio of CD4of CD4++ helper T cells to CD8 helper T cells to CD8++ cells.cells.

Children are prone to recurrent upper and lower Children are prone to recurrent upper and lower respiratory infections and respiratory infections and an increased risk of an increased risk of malignancy. malignancy.

Death from lymphoma is commonDeath from lymphoma is common

Ataxia Telangiectasia

TELANGIECTASIS

Wiskott-Aldrich SyndromeWiskott-Aldrich Syndrome

X-linkedX-linked, combined immune deficiency, combined immune deficiency Thrombocytopenia, eczema and recurrent infectionsThrombocytopenia, eczema and recurrent infections Sinopulmonary, herpes group viruses and Sinopulmonary, herpes group viruses and

occasionally Pneumocystisoccasionally Pneumocystis Few, small plateletsFew, small platelets; ; elevated IgEelevated IgE, , reduced IgMreduced IgM Defect in cytoskeletal organization by WASp (wiskott Defect in cytoskeletal organization by WASp (wiskott

Aldrich Syndrome protein)Aldrich Syndrome protein)

Wiskott-Aldrich SyndromeWiskott-Aldrich Syndrome Patient has decreased IgM and elevated levels of IgA and Patient has decreased IgM and elevated levels of IgA and

IgE. IgE. T-cell dysfunction is initially mild then progressively T-cell dysfunction is initially mild then progressively

worsens making child susceptible to Hodgkin’s disease worsens making child susceptible to Hodgkin’s disease and lymphomaand lymphoma

They are also susceptible to infections (including septicemia They are also susceptible to infections (including septicemia and meningitis) caused by and meningitis) caused by encapsulated microorganismsencapsulated microorganisms

Signs and symptomsSigns and symptoms:: eczemaeczema chronic infectionschronic infections low platelet counts low platelet counts

X-linked lymphoproliferative disorderX-linked lymphoproliferative disorder (XLP or Duncan Disease) (XLP or Duncan Disease)

1 in 100,00001 in 100,0000 Age of onsetAge of onset: 2.5 yrs old, older reported: 2.5 yrs old, older reported Unique predisposition to uncontrolled infection with Unique predisposition to uncontrolled infection with Epstein Epstein

Barr virusBarr virus EBV inducesEBV induces- fatal/severe infectious mononucleosisfatal/severe infectious mononucleosis- Secondary agammaglobulinemiaSecondary agammaglobulinemia- LymphomaLymphoma- Bone marrow failureBone marrow failure Defect in SAP- Defect in SAP- interferesinterferes with with NKNK and and CD8+ CTL CD8+ CTL functionfunction

- - Classified as a Classified as a phagocytic disorderphagocytic disorder, but most likely , but most likely represents represents an abnormality of T cell an abnormality of T cell function function (dysregulated (dysregulated cytokine & Igcytokine & IgEE production) production)- - Candida infections and infections due to pneumocystis, Candida infections and infections due to pneumocystis, cryptocoocuscryptocoocus- - Recurrent pyogenic infections with massively elevated IgRecurrent pyogenic infections with massively elevated IgEE levelslevels- - Recurrent sinopulmonary infections, Recurrent sinopulmonary infections, pneumatoceles, pneumatoceles, severe atopic dermatitissevere atopic dermatitis- - S.aureusS.aureus most common pathogen most common pathogen

Hyper-IgE syndrome (Job Hyper-IgE syndrome (Job syndrome)syndrome)

LABORATORY EVALUATION OF LABORATORY EVALUATION OF IMMUNODEFICIENCY DISORDERSIMMUNODEFICIENCY DISORDERS

Routine investigationsRoutine investigations:: Total and differential leucocyte countsTotal and differential leucocyte counts Absolute lymphocyte countAbsolute lymphocyte count

Normal result rules out T- cell defectNormal result rules out T- cell defect Platelet count and morphologyPlatelet count and morphology

Normal result rules out WASNormal result rules out WAS

Screening testsScreening tests

Diagnosis Diagnosis

Treatment Treatment Bone marrow transplantBone marrow transplant, which , which

provides a new immune system to the provides a new immune system to the patient. patient.

Gene therapy Gene therapy treatment of SCID has treatment of SCID has also been successful in clinical trials, also been successful in clinical trials, but not without complications.but not without complications.

Enzyme replacement Enzyme replacement therapy.therapy.

Treatment for SCID  Treatment for SCID  

Preventing infectionsPreventing infections Live Virus Vaccines And Non-Irradiated Live Virus Vaccines And Non-Irradiated

Blood Are Dangerous.Blood Are Dangerous. Enzyme therapy for ADA deficiency SCIDEnzyme therapy for ADA deficiency SCID

The standard treatment for ADA deficiency SCID is The standard treatment for ADA deficiency SCID is treatment with a form of the ADA enzyme called treatment with a form of the ADA enzyme called PEG-PEG-ADAADA..

Treatment with PEG-ADA is effective in about 90% of Treatment with PEG-ADA is effective in about 90% of children. However, despite PEG-ADA therapy, some children. However, despite PEG-ADA therapy, some children continue to require children continue to require IVIG treatmentsIVIG treatments..

Stem cell transplantationStem cell transplantation

The most common treatment The most common treatment for for SCIDSCIDis is STEM CELL TRANSPLANTATIONSTEM CELL TRANSPLANTATION, which has , which has

been successful using either a matched related been successful using either a matched related or unrelated donor, or a half matched donor, who or unrelated donor, or a half matched donor, who would be either parent.would be either parent.

HLA-matched bone marrow or cord bloodHLA-matched bone marrow or cord blood transplantation from transplantation from unrelated donors unrelated donors has has

also been used successfully to treat SCID, also been used successfully to treat SCID, and and

the immune reconstitution after these types the immune reconstitution after these types of transplants is often better than when a of transplants is often better than when a half-matched parent is a donorhalf-matched parent is a donor

Gene therapyGene therapy Gene therapy has been attempted as an alternative Gene therapy has been attempted as an alternative

to the bone marrow transplant. to the bone marrow transplant.

Transduction of the missing gene to hematopoietic Transduction of the missing gene to hematopoietic stem cells stem cells using viral vectors is being tested in ADA using viral vectors is being tested in ADA SCID and X-linked SCID. SCID and X-linked SCID.

In 1990, four-year-old In 1990, four-year-old Ashanthi DeSilva Ashanthi DeSilva became the became the first patient to undergo successful gene therapy. first patient to undergo successful gene therapy.

Gene therapy Gene therapy

TREATMENT FOR SCIDTREATMENT FOR SCID

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CharacteristicT- cell defectB- cell defectGranulocyte defect

Complement defect

Age of onset of infection

Early; 2-6 months

After 5-7 months

Early onset at birth

Any age

Specific pathogens

Mycobacteria,Viruses, Fungus like Candida and parasites

Pyogenic bacteria mainly Streptococci,StaphylococciHemophilusenteroviruses

Bacteria; StaphylococcusPseudomonasKlebsiella

Bacteria

Systemic effectsFailure to thrive,Extensive mucocutaneous Candidiasis

Recurrent sinopulmonary infectionsMalabsorptionEnteroviral encephalitis

Skin abscesses, impetigo, cellulitis

Recurrent sinopulmonary infectionsMeningitis

Special featuresGVHD, Post vaccination disseminated BCG or VaricellaHypocalcemic tetany in infancy

AutoimmunityLymphomaThymomaPost vaccination paralytic polio

Prolonged attachment of umbilical cordPoor wound healing

Autoimmune diseases

Key PointsKey Points High index of suspicionHigh index of suspicion Thorough history and complete physical Thorough history and complete physical

examination is a mustexamination is a must Begin with screening tests Begin with screening tests and and

approperiate additional testing as requiredapproperiate additional testing as required Teach patients how to Teach patients how to avoid infections avoid infections and and

do required preventive measuresdo required preventive measures Early diagnosis and prompt treatment Early diagnosis and prompt treatment

could be life savingcould be life saving

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