Primary Immunodeficiencies Dr. Katia Sitnitskaya

Primary Immunodeficiencies

Dr. Katia Sitnitskaya

Innate immunity

• Complement: alternative pathway

• Phagocytes: - neutrophils - macrophages

• Natural killers

AG-specific immunity

• Complement: classical pathway AG + AB

• T cell response

• B cell: AB production

Host defenseHost defense

US: how many we are talking about ?

Most common ?

Complement cascade you

DON’T HAVE TO

remember

Complement: - opsonization: C3b, C5b- opsonization: C3b, C5b - chemotaxis: C3a, C5a - chemotaxis: C3a, C5a

- membrane attack: C5-9 - membrane attack: C5-9

ChemotaxisChemotaxisOpsonizationOpsonization

Complement deficiencies: very rare

(-) opsonins(-) opsonins

++

chemotaxischemotaxis

Pyogenic Pyogenic

infectionsinfections

Complement deficiency

• C5-9 “terminal pathway” deficiency: 40% relapse of Meningoccal infection

• 3 – 5% of cases of Meningococcal infection = complement deficiency

• AB-sensitized sheep RBC: measurement of total hemolytic c. by classical pathway (CH50)

• Unsensitized rabbit RBC; measurement of total hemolytic c. by alternative pathway (AH50)

Deficiency Mechanism Infections CH50

C2 C2 = most common opsonins Pyogenic in 1/5

(SLE)

< 10%

Properdin (Xp11)Properdin (Xp11) opsonins Pyogenic NormalNormal(AH50 low)(AH50 low)

C5 - 8C5 - 8 chemotaxis

membrane attack

Recurrent N.men < 10%

C9C9 membrane attack Recurrent N.men 50%

Phagocytic Phagocytic disordersdisorders

Phagocytic disordersPhagocytic disorders

LADLAD

““Indigestion” = CGD, Chediak-HigashiIndigestion” = CGD, Chediak-Higashi

LAD:LAD:- the defect is a lack of a neutrophil adhesion molecule = no emigration into tissues. - presents with delayed separation of the umbilical cord, recurrent SBIs, leukemoid reactions

Phagocytic Disorders: 1. “commuting”Phagocytic Disorders: 1. “commuting”

Leukocyte adhesion deficiencyLeukocyte adhesion deficiency (LAD)(LAD)

A. Normal neutrophils aggregate

B. Neutrophils from a patient with LAD type 1 fail to aggregate in vitro

C. Patients with LAD type 1 have periodontitis periodontitis & recurrent GI, GU, and respiratoryrecurrent GI, GU, and respiratory infections infections

Congenital agranulocytosis Congenital agranulocytosis

Kostmann DiseaseKostmann Disease

• AR, 1: 1 000 000

• An abnormal G-CSF–induced intracellular signal transduction ?

• ANC < 500/mmANC < 500/mm33 + normal WBC count because of the monocytosis.

• Abnormal CD64+ (FCgRI receptor) on neutrophils

• Mild anemia may be present from chronic inflammation.

• + Hyper--globulinemia.

• Mortality rate without Tx: 70% within the 1-st year of life

• Tx: failure of G-CSF BMT, or stem cell transplantation.

1. NADPH oxidase catalyzesreduction of O2 to

superoxide anion (O–•2 )superoxide anion (O–•2 ) 2. Superoxide dismutase convert it to H2O2

3. Neutrophil-derived myeloperoxidase (MPO) converts H2O2 into a

HOCl–bleach Cl2

Phagocytic Phagocytic disordersdisorders

Clinical Features of CGDClinical Features of CGD

A. Inflammation of the nares.

B. Large granuloma in the neck

C. Severe gingivitis

D. An esophageal stricture caused by a granuloma. Resolution after treatment with CSs

Chediak-Higashi syndromeChediak-Higashi syndrome

• AR, the long arm of chromosome 1

• The lysosomes fail to fuse with the phagosome. • Neutropenia + diminished chemotaxis + giant lysosomes

• Dx: chemotaxis assay

• Decreased NK functions.

• The platelets are abnormal (easy bruising).

• Oculocutaneous albinism, photophobia, enterocolitis and peripheral neuropathy.

• BMT has been used with excellent results in several cases.

• 85% of children with CHS, develop lymphoma-like condition which generally conduces to death.

• Prenatal Dx: giant neutrophil granules in the fetal blood.

Myeloperoxidase deficiency

• Common 1 : 2000, AR • Dercreased intracellular killing (no bleach)

• Absence of myeloperoxidase enzyme in neutrophil and monocyte granules.

• MPO deficiency + diabetes mellitus = Candidal sepsis + osteo

• Most patients are asymptomatic

• Dx: chemoluminescence test• Vacuolized neutrophils

Phagocytic disodersPhagocytic disoders

A. Normal peripheral blood smear

B. Peripheral blood smear from a patient with the Chédiak–Higashi syndromeChédiak–Higashi syndrome: large perinuclear granules.large perinuclear granules.

C. Peripheral-blood smear from a patient with agranulocytosisagranulocytosis: the cytoplasm is pale, no granules are present, and nuclei are notched and hyposegmented.

D. Nitroblue tetrazolium test (NBT) in normal neutrophilsNitroblue tetrazolium test (NBT) in normal neutrophils: phagocytosis results in dark-blue staining of the cytoplasm

E. NBT in neutrophils from a patient with CGDNBT in neutrophils from a patient with CGD: there is no phagocytosisno phagocytosis = no dark-blue cytoplasmic staining.

F. A hair hair from a patient with the Chédiak–Higashi Chédiak–Higashi syndrome in which giant granulesgiant granules are present, ( normal hair on thr right).

Phgocytic disorders summaryPhgocytic disorders summary

Common infections with GN and catalase (+),

like Staph. aureus, Pseudomonas a. + Aspergillus.

LYMPHOCYTE DIFFERENTIATION

THY

Ag

T ,T ,T ...H C S/R

Hematopoeiticstem cell

CommonLymphocyte

Precursor

Pre-B

Pre-T

B

T

IgM...

RBC

GranulocytesMonocytes

Platelets

CR

Ab-forming cells

T-effectorT - cells

CR

H,C,S

CR = complement receptor; , = membrane IgM and IgD

“Central” immunodeficiencies: bone marrow / thymic events

3. Severe Combined ImmunoDeficiency (SCID): multi-modal 3. Severe Combined ImmunoDeficiency (SCID): multi-modal

2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q

1. Bruton’s 1. Bruton’s -globulinemia: XR, chrom. Xq22-globulinemia: XR, chrom. Xq22

3311

22

T cell disordersT cell disorders

Severe combined ImmunoDeficiency (SCID)Severe combined ImmunoDeficiency (SCID)

SCIDSCID

Loss of the MHC molecule =

“Bare lymphocyte syndrome”:

no recognition of other cells

SCIDSCIDThe only host defenses are:The only host defenses are:

- Complement

- Phagocytosis

Maintenance:Maintenance:

- Bactrim Px, Azithro Px

- IVIG

Salvage:Salvage:

- Recombinant ADA injections

- BMTBMT

DiGeorge Syndrome: DiGeorge Syndrome: “CATCH-“CATCH-22”22”

• Sporadic microdeletion of 2222q

• Hypertelorism, down-slanted eyes, + cleft palate (“midline defects”)

Developmental defect of the 3-d & 4-th pharyngeal pouchesDevelopmental defect of the 3-d & 4-th pharyngeal pouches• No thymus = low T cell counts• No parathyroid glands = hypo-Ca-emic seizures• CV: interrupted aortic arch & truncus arteriosus

• Treatment: thymus transplantTreatment: thymus transplant

CCardiac malf.

AAbnormal face

TThymic hypopl.

CCleft palate

HHypo-Ca-emia

Ataxia-TelangiectasiaAtaxia-Telangiectasia

• AR, chromosome 11• 1 case in 100,000 births

• Single gene mutation results in impaired repair of DNA damage = cancer in1/4 ( lymphoma)

• Usually presents in the 2-d year of life as a lack of balance and slurred speech.

• Ocular telactasia before age of 6. Mild MR in 1/3

• Progressive cerebellar degeneration (CT: atrophy) + immunodeficiency in 2/3 + radiosensitivity (x-ray)

• AFP, may be small thymus, dys--globulinemia ( Ig G2,4 & A)

Wiscott-Aldrich diseaseWiscott-Aldrich disease

• WASP gene on Xp11 chromosome = X-linked recessive

• Defective cytoskeleton of T cells and platelets

• TCP + Eczema + recurrent sino-pulmonary infections, HSV / CMV, PCPTCP + Eczema + recurrent sino-pulmonary infections, HSV / CMV, PCP

• Labs: small Plt, T cells, B cells, Ig A & E, specific ABs

• Tx: IVIG BMT

• Pre-natal Dx: EM of fetal lymphocyte

Monocytes and macrophages bind

IFN- IFN- activation:

1. production of hydrogen peroxide (H2O2)

2. synthesis & release ofsynthesis & release of IL-12IL-12

& tumor necrosis factor (TNF)

A. Resolving mycobacterial infection with normal granuloma formation

B. An AR mutation of the IFN- receptor : mycobacteria survive in macrophages

C. Same patient: no granuloma

IL-12 produced by macrophages and dendritic cells in the presence of a pathogen,

binds to its receptors on T cells and NK cells

inducing the release of IFN-

IL-12 receptor deficiencyIL-12 receptor deficiency

T cell deficiencies: summaryT cell deficiencies: summary

B cell disordersB cell disorders

Bruton’s X-linked A-g-globulinemiaBruton’s X-linked A-g-globulinemia

• Absence or deficiency of a Bruton’s tyrosine kinase: maturation arrest of pre-B cells • Levels of all Ig levels are less than 10% of normal.

• Infections start after 5 months of age: capsulated ( H. influenzae, Strep. pneumoniae, Giardia lamblia, ECHO viruses)

. Tiny tonsils,

• Molecular confirmation of the Dx: fluocytometry

• Treatment: IVIG

Selective Ig A deficiencySelective Ig A deficiency

• Most common immunodeficiency: 1: 700 in US • Some cases are AR.

• 1 : 300 in atopic population

• Majority of patients are clinically normal

• Ig A < 5Ig A < 5: recurrent / chronic sinopulmonary, GI, GU infections

• Allergy, GI (celiac disease, UC), JRA, SLE

• IgG is c/indicated unless IgG deficiency also presentIgG is c/indicated unless IgG deficiency also present

Hyper-E syndromeHyper-E syndrome

• Pruritic dermatitis (eczema)

• Recurrent staphylococcal abscesses of skin, lung, joints, etc.

• Eosinophilia of blood and sputum

• Ig G, M, A usually normal

• Extremely high Ig E > 1000 , high Ig D

• Diminished response to immunization

• Poor cellular and humoral response to neoantigens

• Tx: IVIG BMT

Hyper-M Hyper-M X-linked disorderX-linked disorder

T helperT helper

B cellB cell

Patients have abnormal CD4 ligand on T cells, and can not properly signal B cells

Thus, this is really a T cell Thus, this is really a T cell problem; the B cells work fineproblem; the B cells work fine

Block in switching from Ig M Block in switching from Ig M to IgG, IgA, IgE to IgG, IgA, IgE

Hyper-M Hyper-M X-linked disorderX-linked disorder

• X-linked recessive: Xq26 + sporadic cases

• Recurrent pyogenic, mostly sinopulmonary, infections

• Sclerosing cholangitis

• Increased incidence of autoimmune and lymphoproliferative disorders

• Low Ig G & Ig

• Neutropenia, TCP, anemia

• Tx: IVIG

Common Variable Immune Deficiency Common Variable Immune Deficiency (CVID)(CVID)

• AD / X-linked

• Onset after 10 y., recurrent sinopulmonary infections & other pyogenic

Lymphadenopathy and splenomegaly may be present

• IL-2, IFN-IL-2, IFN-CD40L (defective CD4 function )CD40L (defective CD4 function )

• IgG < 50% (< 250), Ig A & M

• No specific Ab production / no response to vaccinesNo specific Ab production / no response to vaccines

• Anti - B cell autoantibodies

• Patients may have a higher occurrence of atopic / rheumatalogic diseases, lymphoid hyperplasia

• Treatment: IVIG to keep IgG > 400Treatment: IVIG to keep IgG > 400

Transient hypo-Transient hypo- infantorum infantorum

• Delayed onset of IgG synthesis, but always > 200

• Physiological nadir of IgG level 430 – 660 @ 4 – 12 mo. Of agePhysiological nadir of IgG level 430 – 660 @ 4 – 12 mo. Of age

• Onset of symptoms coincides with decline in matrnal IgG level

• Normal levels of Ig A & M

• Normal IgG response to immunizationNormal IgG response to immunization

• Mature B cells & plasma cells are present

• Resolves by 24 – 36 months of age Resolves by 24 – 36 months of age

B cell disorders summaryB cell disorders summary

Examples of Infectious Agents in Different Types of Immune Deficiencies

Pathogen TypePathogen Type T-Cell DefectT-Cell Defect B-Cell DefectB-Cell Defect Granulocyte Granulocyte DefectDefect

Complement Complement DefectDefect

BacteriaBacteria Bacterial Sepsis Streptococci, Staphylococci, Haemophilus

Staphylococci, Pseudomonas

Neisseria,pyogenic bacteria

VirusesViruses CMV, EBV, varicella, chronic respiratory & GI infections

Enteroviral encephalitis

Fungi & Fungi & ParasitesParasites

Candida, PCP

Giardiasis Candida,Nocardia, Aspergillus

Special Special FeaturesFeatures

OIsfailure to clearinfections

Recurrent sinopulmonary infections, sepsis, chronic meningitis

Warning Signs of Primary Immunodeficiency Disorders

Medical history

• > 8 ear infections / year • > 2 serious sinusitis / year • > 2 pneumonias / year • > 2 deep-seated infections, or infections in unusual areas

• Recurrent deep skin/organ abscesses

• Need for IV ABx to clear infection • Infections with unusual /opportunistic organisms

• Family Hx of primary immunodeficiency

Physical signs

• Poor growth, FTT

• Absent lymph nodes or tonsils • Skin lesions: telangiectasias, petechiae, lupus-like rash

• Ataxia (ataxia-telangiectasia) • Oral thrush after1 year of age • Oral ulcers

Table 1. Indications for immune evaluation

Infection frequency Infection type

Single episode OsteomyelitisSeptic arthritisMeningitis

Two episodes SepsisPneumonia

Multiple episodes SinusitisBronchitisPneumonia

D. Dube et al, POSTGRAD MED, 2002

Table 4. Tests of immunologic functions

Initial Advanced

Cellular immunity

CBC: ANC & ALC Lymphocyte subsets Candida skin test

LPA, CTL activity, Cytokine productionADA level

Humoral immunity

Serum Ig G, A, M, E Diphth / Tetanus and Pneumoc. titers IgG 1 - 4 subclasses B-cell quantitation In-vitro AB production

Phagocytic function

CBC, NBT test FACS = H202 (for CGD) Chemoluminescence assay (for M-p-o) Chemotaxis assay (for C-H) CD 11 / 18 (LAD)

Complement Total HemolyticComplement assay:

Classical = CH50

Alternative = AH50

Quantitation of individual complement components and regulatory molecules

Serum opsonic and chemotactic assays

Workup for suspected P.I.D.

IVIG is indicated for: - Bruton’s a--globulinemia

- Hyper-M & Hyper-E

- CVID & Ig subcl. = if NO SPECIFIC Abs !

- SCID & Wiscott-Aldrich

Indications for BMT:

• Hyper-E syndromeHyper-E syndrome

• SCIDSCID

• Wiscott-AldrichWiscott-Aldrich

• Chediak-HigashiChediak-Higashi

• Kostmann DiseaseKostmann Disease

Selected causes of secondary immunodeficiency diseases

Causes Examples

Malnutrition Protein / energy malnutrition, malabsorption syndrome

Infection HIV, congenital CMV / EBV / Toxoplasma

Drugs Corticosteroids, Phenytoin, Sulfasalazine, Cytotoxins

Chronic medical conditions Sickle cell disease, cystic fibrosis

Malignancy ALL, AML, lymphomas

Protein (Ig) loss Protein-losing enteropathy, nephrotic syndrome

Chromosomal syndromes Down syndrome