1. In the Name of God the Merciful the Bneficient

2. Overview of Primary
Immunodeficiency
Disorders(PIDs)
Mostafa Moin MD
Professor of Allergy & Clinical Immunology
Immunology, Asthma & Research Institute
IAARI
Tehran Univesity of Medical Sciences
1392- 2014

3. Key Roles of Immune System
Prevent and control infection
Prevent and control autoimmune diseases
Prevent and control malignancy
Prevent and control allergic diseases
Prevent and control graft-versus-host (GVH)

4. Host Immune Defense Mechanisms
Non-specific -Innate
Barriers
– Skin
– Secretions (mucous,
tears, saliva)
– Mucociliary clearance,
peristalsis
Phagocytes
– Neutrophils
– Macrophages
Complement
Cytokines
Specific - Acquired
 Humoral (antibodies)

Cellular
(lymphocytes)

5. Innate and Acquired Immunity
Innate
Acquired
Ag specificity
no
yes
Magnitude (10, 20)
same
higher (20 > 10)
Memory
no
yes
Key components
PMN, NK T, B lymphocytes
C’, barriers APCs
Cytokines,
Chemokines,
Adhesion molecules

6. Types of Immuno-deficiencies
Defects in some components of the immune system
- Gene defect
6

7. Clinical Features of Primary Immunodeficiency
Increased frequency, severity
and duration of infection
Unexpected complications or
unusual manifestations of
infection
Infection with organisms normally
considered of low pathogenicity
Noninfectious manifestations in
gastrointestinal, endocrinologic,
hematologic organ systems

8. Clinical Findings in Primary Immunodeficiency
Recurrent respiratory infection
Persistent sinus infection
Paucity of lymphoid tissue
Failure-to-thrive in infants
Skin lesions (rash, pyoderma, eczema,
telangiectasia)
Oral and perineal candidiasis
Diarrhea and malabsorption

9. Accurate diagnosis and
classification of PID is necessary
WHY?
To decide on appropriate clinical management
To enable ininformed genetic counseling
To permit the systematic collection of data on PID
through registries that will facilitate further study
of these rare diseases
To highlight the advances in gene therapy
9

10. PIDs Prevalence

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Texbooks report 1 in 10000
1999 U.S. Immunodeficiency Foundation
Survey found 1 in 5000
2007 telephone survey of 27000
household members found 1 in 1200
Antibody deficiencies account for
approximately 65% of PID cases

11. PID Classification:2011-IUIS
International Union of Immunological Societies
New York City, May 31-June 1, 2011
Table 1 | Combined immunodeficiencies
Table 2 | Well-defined syndromes with immunodef.
Table 3 | Predominantly antibody deficiencies
Table 4 | Diseases of immune dysregulation
Table 5 | Congenital defects of phagocyte number,
function, or both
Table 6 | Defects in innate immunity
Table 7 | Autoinflammatory disorders
Table 8 | Complement deficiencies

14. Immunopathologic Basis of PID

15. Four Major Host Defense Deficiencies
1. B-cell (humoral) immunodeficiencies
2. T-cell or combined
immunodeficiencies
3. Phagocyte disorders
4. Complement disorders

16. IgG Antibody Levels Vary with Age

17. Deficient Serum Antibody Level
 Rules of thumb:
-Quantitative IgG< 1000 is abnormal
-Quantitative IgM< 100 is abnormal
-Quantitative IgA< 10 is abnormal

18. Symptoms of antibody deficiency

Recurrent upper and lower respiratory
infections

Severe bacterial infections with
polysaccharide encapsulated bacteria

Paucity of lymph nodes and tonsils

Immune cytopenias

Autoimmunity - arthritis, SLE

Diarrhea and malabsorption
 Malignancies

19. Antibody Deficiency Infectious Organisms
Bacteria: pneumococcus, H. flu,
meningococcus, Staph aureus,
Pseudomonas, Campylobacter
Mycoplasma, ureaplasma
Viruses: enteroviruses, rotavirus
Protozoa: giardia, cryptosporidium
Common organisms are still the most
common - but typically more severe and
difficult to treat

20. Primary Antibody Disorders
Agammaglobinemias (XL,AR)
Common Variable Immunodeficiency
IgA deficiency
IgG subclass deficiency
Specific antibody deficiency
Transient hypogammaglobinemia of
infancy

21. Antibody def.-Bruton's disease
 X-linked agammaglobulinemia (XLA)
 Marked reduction in all Ig classes, B cell numbers
& production of specific antibodies
 Normal number and function of T cells
 Defect in Bruton`s tyrosine kinase gene , B cell
development “frozen” at early precursor stage
 Beginning after 6 months of age,recurrent
sino-pulmonary Infections

22. Antibody def.-Bruton's disease
Diarrhea due to giardia, Invasive infections
(sepsis, meningitis) due to encapsulated bacteria
(pneumococcus, meningococcus)
 Skin/soft tissue infections
 Generally no increased severity of viral infections,
but at risk for chronic multisystem inf. due to
enteroviruses (including dermatomyositis- like
synd. , hepatitis,meningoencephalitis)


23. Antibody: Common variable
immunodeficiency - CVID

Onset usually in 2nd to 4th decade of life
Slow decline in all classes of immunoglobulin
Recurrent sinopulmonary infections (usually
bacterial in origin)
Gastrointestinal, endocrine, hematologic and
autoimmune disorders can be associated
May follow Epstein-Barr infection
Increased incidence of
lymphoreticular malignancies
Genetic defect?

24. Antibody: IgA deficiency

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IgA< 5 mg/dl
Most common (1:400- 1:1000)
Often asymptomatic, may have recurrent
sinopulmonary infections
May co-exist with IgG subclass deficiency
Allergy / autoimmunity
No treatment (only for infections)
Genetic defect?

25. Antibody deficiencies

-
-

-
-
Transient hypogammaglobulinemia of infancy
Maturational delay with low, persistent nadir in Ig
production: normal event in preterm infants
Usually recurrent sinopulmonary infections
Usually normal B cell number and response to
immunization
IgG subclass deficiency
Commonly overdiagnosed but may be significant if
specific antibody production also low
IgG2, 4-infection with encapsulated bacteria
IgG3-recurrent respiratory infections
May occur in association with IgA deficiency and
evolve to common variable immunodeficiency

26. Antibody: Hyper IgM Syndrome


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X-linked, defect in CD40 ligand expression (CD1540)
1: 500000, 90% by age 4 yrs old
Recurrent sinopulmonary and invasive infections due to
encapsulated bacteria
Recurrent neutropenia associated with oral ulcers and perirectal
abscesses
Opportunistic infections caused by Pneumocystic jiroveci, CMV,
adenovirus, Cryptococcus, and mycobacteria
Chronic diarrhea due to Giardia or to Cryptosporidium,
Salmonella, or Entamoeba histolytica
Markedly reduced IgG & IgA; high or normal IgM
Normal numbers of B and T cells

27. Secondary hypogammaglobulinemia


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Medications, especially anticonvulsants
Protein-losing enteropathy
Nephrotic syndrome
Iymphoproliferative disease
Non-Hodgkin`s Iymphoma
Multiple myeloma

28. T cells/combined immunodeficiency
CD4+ cells:
– DTH
– Helper function for
• Cellular cytotoxicity
• Ig synthesis
CD8+ cells:
– T-cell cytotoxicity
– T suppressor cell

29. T cells/combined immunodeficiency



-

T cells required for orchestrating adaptive immunity
Loss of CD4 (helper) T cells results in combined cellular
and humoral immunodeficiency, even if B cells are
normal
Deficiency results in infections with:
viruses-particularly herpes group
Intracellular bacteria-e.g., Mycobacteria, Listeria
Protozoans-pneumocystis, toxoplasma, cryptosporidium,
giardia
Antibody production to newly encountered microbes also
compromised

30. Functional Classification T cells/combined Id.

31. Severe Combined Immunodeficiency(SCID)


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Presentation usually< 6-12 mo age
Opportunistis infections and recurrent
pyogenic infections, chronic
diarrhea , FTT, eczema
Male: female 4:1 (most common
form is X-linked)
Often fatal befor 1 year of age if untreated
Decreased number of T cells, variable
numbers of B cells, poor proliferation to
mitogens
Low or absent IgG and IgA

32. Severe Combined Immunodeficiency(SCID)



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
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Severe deficits in cellular and humoral
immunity
Classified by inheritance pattern and pattern
of lymphocytes present
X-linked:
IL-2Rγ chain-more than half of all cases
Same γ chain found in many interleukin
receptors
Autosomal recessive:
RAG, ADA/PNP, JAK3, IL-7Ra, ZAP-70

33. Severe Combined Immunodeficiency(SCID)
 X-linked
 T- , NK, B+ phenotype
 60% of SCID, gene identified in 1992
 Defective gene encodes the cytokine common gamma chain
 Mild lymphopenia (mean ALC 1500)
 40% have a positive family history
 Adenosine Dearninase (ADA) deficiency-AR
 15% of all SCID
 Early onset
 Profound lymphopenia
 Clinically heterogeneous
 ADA is a widely expressed enzyme, involved in purine
metabolism
 Build up of toxic metabolic products toxic to T cell development

34. Severe Combined Immunodeficiency(SCID)
RAG1 and RAG2 Deficiency- AR
 T- , B-, NK+
 10% of SCID genes identified in 1989
 RAG1 and RAG2 form a heterodimer that is required to initiate
VDJ recombination
 Moderate lymphopenia (mean ALC 1000)
 Amino acid substitutions can cause Omenn Syndrome (SCID
with hyper-eosinophilia)
JAK-3
 T-, NK-, B+ phenotype
 7% of SCID gene identified in 1994
 Defective gene encodes a lyrosine kinase activated by the
cytokine common gamma vhain
 Mild lymphopenia (mean ALC 1500)

35. Other Forms of T cell/combined
Immunodeficiency
Purine nucleoside phosphorylase (PNP) deficiency –AR
 Rare form of cellular deficiency associated with defective Ab
production and autoimmunity
 May present later in childhood
 2/3 of patients develop progressive neurological manifestations
Ataxia- Telangiectasia- AR
 Mutation in protein required for DNA repair
 Ocular telangiectasias, cerebellar ataxia
 Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4
and Tcell deficits
 Risk of Malignancy in patients and carriers

36. Other Forms of T cell/combined
Immunodeficiency
DiGeorge Syndrome
 Developmental field defect of 3rd and 4th branchial
arches due to chromosomal deletion (22q)
 Cardiac/great vessel > parathyroid > thymic defect
 Severe hypocalcemia
 Charactristic facies: mandibular hypoplasia,
hypertelorism
 Great variability in the severity of T cell abnormality
(<1% have thymic aplasia with absence of T cells)

37. Other Forms of T cell/combined
Immunodeficiency
 Wiskott-Aldrich Syndrome
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X-linked partial combined immune deficiency
Thrombocytopenia, eczema and recurrent infections
Sinopulmonary, herpes group viruses and
occasionally Pneumocystis
Few, small platelets; elevated IgE, reduced IgM
Defect in cytoskeletal organization by WaSp (wiskott
Aldrich Syndrome protein)

38. X-linked lymphoproliferative disorder
(XLP or Duncan Disease)
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1 in 1000000
Avg age of onset: 2.5 yrs old, older reported
Unique predisposition to uncontrolled infection with
Epstein Barr virus
EBV induces
fatal/severe infectious mononucleosis
Secondary agammaglobulinemia
Lymphoma
Bone marrow failure
Defect in SAP- loss interferes with NK and CD8+ CTL
function

39. Defects in Phagocytes

Defects in phagocytes generally associated
with recurrent or severe/ unusual pyogenic
infections

S.aureus, Serratia, Burkholderia, Nocardia, chromobacterium, fungi
(esp, Aspergillus)

Tend to occur at interfaces between host and
environment-skin, respiratory, Gl or GU tracts
Failure to kill organism results in localized
infection and abscess (CGD)
Failure to mobilize WBCs to tissues
(LAD,Chediak- Higashi) may result in rapid
spread of infection systemically



40. Defects in Phagocytes
Chronic Granulomatous Disease (CGD) –
1: 200000
Due to genetic deficencies in NADPH oxidase for
neutrophil oxidative burst required for intracellular killing
X-linked most common (65-70%) also AR
Mean age of presentation 0-8 yrs,older age possible
Infections with catalase positive organaims
(S.aureus, B.Cepacis, S.marcescens, aspergillus app.,Nocardia app)

Granulomatous inflammation-lymphadenitis,osteomyelitis,
visceral abscess, pneumonia
Prophylaxis with TMP-SMX,IFN-ү,Itraconazole

41. Defects in Phagocytes

Leukocyte adhesion deficiency
-
-
Failure of neutrophil adhesion and migration
to site of infection due to defect in CD18 (LAD1)
Neutrophilla, recurrent life-threatening infections, little
inflammation at site of inlection
Delayed cord separation, severe periodontal disease

Myeloperoxidase deficiency
-
Failure to generale hypochlorous acid in neutrophil,AR
Most common inherited neutrophil disorder
Rarely develop serious infection-diabetics at risk for
fungal infections
-
-

42. Defects in Phagocytes
 Chediak-Higashi syndrome
AR,
results in abnormal neutrophil granule
formation-abnormal chemotaxis and
degranulation with delayed killing
Recurrent cutaneous and respiratory infections,
progresses to malignancy
 IRAK4 deficiency
Important signaling molecule in Toll-like
receptor4 pathway in macrophages
Deficiency leads to recurrent, life-threatening
staphylococcal and pnemococcal infections

43. Defects in Phagocytes

Hyper-IgE syndrome (Job syndrome)
- Classified as a phagocytic disorder, but most likely
represents an abnormality of T cell function(dysregulated
cytokine & IgE production)
- Candida infections,occult infections due to pneumocystis,
cryptocoocus
- Recurrent pyogenic infections with massively elevated IgE
levels
- Recurrent sinopulmonary infections, pneumatoceles,
severe atopic dermatitis
- S.aureus most common pathogen

44. Defects in Complement

Defects in complement system lead to
susceptibility to encapsulated organisms
(S.pneumoniae, N.meningitidis) & autoimmunity
(SLE)

Classical pathway:
-
Activated by IgE, IgM, CRP bound to a microbe

MBL pathway:
-
Activited by mannan binding lectin bound to a
microbe

Alternative pathway:
-
Fluid phase activation, amplified on microbe

45. Defects in Complement
Early classical complement deficiencies:
May be associated with recurrent pyogenic infections and or
collagen vascular disease(SLE)
 Alternative pathway deficiencies:
C3- collagen vascular disease and significant infections with
encapsulated bacteria
Properdin deficiency-X-linked, fulminanl/ fatal infections due to a
N.meningitidis
 MBL deficiency:
Autoimmune, worse prognosis for other infections(AIDS),
immunosuppressed patients, liver transplants
 Terminal component deficiencies:
- Associated with infections due to N.meningitidis and
N.gonorrheae, chronic meningococcemla


46. Complement- Acquired Def.
Lack of synthesis:
- Severe liver dysfunction
 Increased consumption:
- Immune complex mediated (SLE)
DIC, endocarditis, disseminated gonococcal infection,
hepatitis
- Some glomerulonephritides- C3 nephritic factor
causes C3 depletion
 Loss:
- Nephrotic syndrome


47. Diagnosis of Primary Immunodeficiency
Medical history
Physical examination
Laboratory testing

48. Primary Immunodeficiency: Infections

49. Diagnosis of Primary Immunodeficiency
History of Symptoms
Birth to 3 months
– Phagocytic cell defects
– Complement defects
– DiGeorge syndrome
3 to 6 months
– Severe combined immunodeficiency (SCID)
6 to 18 months
– X-linked agammaglobulinemia
18 months through adulthood
– Common variable immunodeficiency
– Complement defects

50. Diagnosis of Primary Immunodeficiency
Physical Examination
Growth measurements
Inspection of tonsils
Palpation of lymph nodes
Organomegaly
Skin lesions

51. Diagnosis of Primary Immunodeficiency
Screening Tests
Antibody mediated immunity
– Quantitative immunoglobulins
– IgG subclass determination
– Isohemagglutinins
T-cell immunity
– Total lymphocyte count
– Lateral chest x-ray (infants)
– Delayed hypersensitivity skin
tests (individuals >2 years of
age)

52. Diagnosis of Primary Immunodeficiency
Screening Tests
Neutrophil
– White blood cell count and
differential
Complement
– Total hemolytic complement
test (CH50)
– C3 and C4 concentration

53. Diagnosis of Primary Immunodeficiency
Advanced Tests

54. Management of PID
General treatment
Replacement therapy
Immune reconstruction
Gene therapy

55. General Management of PID
Diet
Avoidance of pathogens (“germ-free” care)
Antibiotics
- use in acute illness
- Prophylactic
Avoid whole blood transfusion in combined
immunodeficiency disorder (GVHR)
Avoid live virus vaccines and BCG

56. Immunoglobulin replacement
Treatment of severe antibody disorders
IVIG
400~ 600 mg/kg/m iv drip
SCIG
Frozen plasma
10ml/kg/month
Caution :
with administration of blood products
if
selective IgA deficiency

57. Specific treatment for cellular deficiency
Bone marrow transplantation
Replacement therapy
- Enzyme replacement
- Gene therapy
- Thymic hormones
- Cytokines
Fetal thymus transplantation
Interferon gamma for CGD
Granulocyte transfusion

58. ‫شكرم‬
THANKS