Primary

Immunodeficiency
Dr. A. Barasa
12102021
 Introduction
• Failure of the immune system to protect a host against infections –
manifests as increased susceptibility to infections

• Unusual frequency or severity of infectious disease

• Immunodeficiencies can be primary (congenital) or secondary

(acquired)
 Introduction
• Inherent immune defect – Inborn Errors of Immunity

• Rare (but commoner than we think)

• Worldwide prevalence 1/1000 (ranges from 1/223 for conditions such as
selective IgA def; to 1/58000 for SCID)

• Classified according to the immune defect

• Often diagnosed in childhood

Primary vs Secondary Immune Deficiencies

Chapel H et al; Essentials of Clinical Immunology, 6e

 PIDs/IEIs
• Heterogenous group of disorders

• Inherent immune defect; poor or absent function in 1 or more immune

system components (Inborn Errors of Immunity)

• Predisposition to Increased frequency and severity of infections

• Immune dysregulation: Autoimmunity, Allergy; Aberrant inflammation;

Lymphoproliferation

• 406 distinct disorders defined phenotypically; 430 single gene defects

• Classified genotypically and phenotypically

 Pathogenesis of PIDs
Monogenic disorders

KEY:

Circles – combined immunodeficiencies

• 1 – SCID

Triangles – predominantly T cell deficiencies

• 2 – Congenital thymic aplasia (DiGeorge Syndrome)
• 3 – SCID: cytokine signalling deficiency
• 9 – T cell signalling defect

Squares – B cell deficiencies

• 4 – X-linked agammaglobulinaemia (Bruton’s)
• 5 -Common variable immunodeficiency (CVID)
• 6 – Selective IgA deficiency
• 7 – Bare lymphocyte syndrome
• 8 – Hyper IgM syndrome

Coico R & Sunchine G; Immunology: a short course; 7e

 2019 IUIS Phenotypic Classification for PIDs
I. Immunodeficiencies affecting Cellular & Humoral Immunity
- SCID (CD3 T cell lymphopaenia)

II. Combined Immunodeficiency with Associated or Syndromic

Features
- Thymic defects e.g. DiGeorge
- Congenital Thrombocytopaenia (AT, WAS)
- CD40 L def
- HIES
 SCID
1. Reticular dysgenesis - defect in mitochrondrial
adenylate kinase, preventing differentiation of
myeloid & lymphoid cells from HSC

2. ADA def – enzyme deficiency leading to defect

in purine metabolism; premature death of
lymphoid lineage due to accumulation of toxic
metabolites

3. RAG1/2 mutations - defective V(D)J

rearrangements

4. Defects in common 𝛾 chain of receptors for IL-

2, -4, -7, 9, -15, -21, causing defective cytokine
signaling

5. Mutations in CD3 chains leading to disruptions

in pre-TCR & TCR signaling
SCID Phenotype is Dependent upon the Gene Defect

Delves PJ et al. Roitt’s Essential Immunology, 13 e

Ataxia Telangiectasia

Burmester GR et al; Color Atlas of Immunology

Congenital Thymic Aplasia (DiGeorge Syndrome)

Burmester GR et al; Color Atlas of Immunology

Wiskott-Aldrich Syndrome

Burmester GR et al; Color Atlas of Immunology

CD40 L Deficiency

No class
switch to
IgG
or IgA
 2019 IUIS Phenotypic Classification for PIDs
III. Predominantly Antibody Deficiencies
- Hypogammaglobulinaemia
- Bc absent e.g. XLA
- Bc >1% e.g. CVID
- Transient Hypogammaglobulinaemia of Infancy
- Selective IgA def
 Primary Antibody Deficiencies
• X-linked agammaglobulinaemia
• Mutation in BTK gene
• Maturational arrest at pre-B stage

• IgA and IgG subclass deficiencies

• Selective IgA deficiency

• Transient
hypogammaglobulinaemia of
infancy Serum immunoglobulin levels and age

Chapel H et al; Essentials of Clinical Immunology, 6e

Common Variable Immunodeficiency (CVID)

Burmester GR et al; Color Atlas of Immunology

 2019 IUIS Phenotypic Classification for PIDs
IV. Diseases of Immune Dysregulation
- HLH
- Syndromes with Autoimmunity
- ALPS
- Immune Dysregulation, Polyendocrinopathy, Enteropathy, XL (IPEX, FOXP3)
- Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy
(APECED; AIRE)
 2019 IUIS Phenotypic Classification for PIDs
V. Congenital Defects of Phagocyte Number, Function or both
- Neutropaenia
- Functional Defects e.g. LAD, CGD

VI. Defects in Intrinsic & Innate Immunity

- Predisposition to Invasive Bacterial Infections e.g. congenital
asplenia
- Predisposition to Parasitic and Fungal Infections – IL-17 def in
CMC, APOL1
- MSMD
- Predominant Susceptibility to Viral Infection
 Phagocyte Defects - Quantitative

Secondary causes of neutropaenia are more common than primary ones

Chapel H et al; Essentials of Clinical Immunology, 6e
 Phagocyte Defects - Qualitative
Deep abscesses,
osteomyelitis

A. Defects in adhesion

Disrupted ability of lecuocytes to

interact with vascular
endothelium

Imparied migration from blood to

sites of infection

B. Impairment in mechanism required

for phagocytosis

Reduced oxidative metabolism

Oculocutaneous albinism
Defective intracellular killing of
Defective chemotaxis micro-organisms
Lysosomes fail to fuse with
phagosomes
Coico R & Sunchine G; Immunology: a short course; 7e
Mendelian Susceptibility to Mycobacterial Diseases (MSMDs)
IL-12
activation &
signaling
pathway

IFN-𝛾 pathway
 2019 IUIS Phenotypic Classification for PIDs
VII. Auto-inflammatory Disorders

VIII.Complement Deficiencies

IX. Bone Marrow Failure

X. Phenocopies of PID
- Associated with Somatic Mutations
- Associated with Autoantibodies
 Complement Deficiencies –
Paroxysmal Nocturnal Haemoglobinuria (PNH)

DAF CD59
defect (protectin)
deficiency

• Mutation in PIG-A gene that encodes 𝛼-1,6-N-acetylglucosaminyl-transferase

• Inability to synthesize the glycosyl phopshatidylinositol anchors

• Rbc membrane deprived of complement control proteins; susceptible to complement-mediated lysis

Delves PJ et al. Roitt’s Essential Immunology, 13 e
 Complement Deficiencies
Defective Disorder Typical Infections
Gene
C1q, C1r, C1s Predisposition to Pyogenic bacteria
immune complex-
mediated autoimmune
disease e.g. SLE

C1 inhibitor Hereditary angioedema -

C2, C3 Predispostiion to Pyogenic bacteria

immune complex-
mediated autoimmune
disease

C5, C6, C7, - Neisseria gonorrhoeae

C8, C9 N. Meningitidis

Chapel H et al; Essentials of Clinical Immunology, 6e

 Distribution of PIDs by Type

Song et al., 2011, Clinical and Molecular Allergy 9:10. doi:10.1186/1476-7961-9-10

 Manifestations of PIDs
Increased susceptibility to infection
• Repeated, unusual or difficult to treat infections

• Multiple courses of (intravenous)

antibiotics/antimicrobials

• Type of infections & their severity depends on

immune defect present; can give a clue to the
immune defect

Autoimmunity

Allergy

Malignancy

Jeffrey Modell Foundation Medical Advisory Board

 Pattern of Infections in PIDs
Organism Antibody Deficiency Combined Immune Phagocyte Defects Complement
Deficiencies Deficiency
Pattern of Ear, sinus, lung, GI Pneumonia, TB, GI, Skin abscesses, Sepsis
Infection mycoses of skin & reticuloendothelial
mucous infections
membranes
Viruses Enteroviruses (XLA) All, esp HHV8, EBV, - -
HSV, HZV, CMV
Bacteria Strep pneumo Also Salmonella, Staph aureus Also N. meninigitidis
H. Influenzae Listeria, Enteric flora (catalase + bacteria) (late components)
(encapsulated bacteria)
Mycobacteria - Non tuberculous Non tuberculous -
including BCG including BCG
Fungi - Candida, Aspergillus Candida -
C. neoformans, H. Aspergillus
capsulatum
Protozoa Giardia P. Jiroveci - -
Toxoplasma
C. parvum
Diagnosis of PIDs – Patient Evaluation
 Diagnosis of PIDs – Laboratory Evaluation
Humoral Immunity Cellular Immunity (T & NK Phagocytosis Complement
(B cell) cell) System
Quantitative IgG, IgA, IgM Absolute lymphocyte count Absolute neutrophil count C3 & C4
Assessment (CBC with differential counts) (CBC with differential
B cell enumeration counts)
(CD19, CD20) Exclude HIV
Flow cytometry – CD11 &
T & NK cell enumeration - CD18 (LAD type 1), CD15a
CD3CD4, CD3CD8, CD16CD56 (LAD type 2)

Qualitative/ Isohaemagglutiin titre DTH – skin tests (tuberculin, Oxidative function CH50 (classical
Functional Candida) (DHR, NBT) pathway)
Assessment Antibody titres to
protein antigen CXR (thymic shadow) Enzyme assays AH50 (alternate
(diphtheria, tetanus) & (MPO, G6PD) pathway)
polysaccharide antigen Enzyme assays
(pneumococcus) (ADA & PNP) Phagocytosis &
bactericidal killing assays
NK cytolysis assays

Mitogen or Ag stimulation

Cytokine production
 Treatment of PIDs
• Antimicrobial prophylaxis

• Replacement of the missing component

• Protein replacement therapy
• IVIG
• Enzymes (e.g. ADA)
• Cytokines (e.g. G-CSF in neutropaenia, IL-2, IFN-𝛾 in CGD)

• Cell replacement therapy – HSCT

• Gene replacement therapy