PRIMARY IMMUNODEFICIENCIES

OVERVIEW OF THE IMMUNE SYSTEM

Innate Immune System Adaptive Immune System

- Macrophage - B lymphocytes
- Neutrophils - T lymphocytes
- Dendritic cells
- Complement System

Functions of the innate immune system:

1. Recognition – receptors on macrophages, neutrophils and dendritic
cells
2. Acute inflammatory response – pathogens are engulfed and killed
intracellularly by macrophages and neutrophils
3. Induction of adaptive immune response – activated antigen presenting
cells migrate to lymphoid organs where antigens are presented to T cells
and B cells
 IMMUNE SYSTEM

• Central lymphoid organs: Thymus and Bone marrow

• Function: Generate lymphocytes
• Bone marrow: Immature B cells develop in bone marrow -> migrate
to peripheral lymphoid organs, where activation by antigens lead to
proliferation and differentiation into antibody producing plasma cells
• Thymus: T cell precursors migrate from bone marrow to thymus ->
Native CD4 and CD8 T cells then enter peripheral lymphoid organs
and differentiate into effector T cells
• Peripheral lymphoid organs (Lymph nodes, spleen,
tonsils): Where naïve lymphocytes meet antigens and initiate
adaptive immune response (macrophage activation or cytotoxic
T cell activity)
 RED FLAGS – WHEN TO SUSPECT PID?

• Recurrent/persistent infections of
unusual severity and affecting
multiple sites
• Opportunistic infections
• Failure to thrive
• Family history of recurrent
infections
 CATEGORIES OF PID

Category example Category example

Combined e.g SCID Defects in IL12-IFNg pathway
immunodeficiencies innate defect
Combined e.g Wiskott Aldrich syndrome, immunity
immunodeficiency with HyperIgE syndromes Auto- Familial
associated or syndrome inflammatory mediterranean Fever
features disorders
Antibody deficiencies e.g Hypogammaglobulinemia, CVID Complement
deficiencies
Diseases of Immune Hemophagocytic Phenocopies of
Dysregulation Lymphohistiocytosis (HLH) PID

Phagocytes (number or Chronic granulomatous disease 2017 IUIS Phenotypic Classification

function) for Primary Immunodeficiencies
 MAIN CATEGORIES OF
IMMUNODEFICIENCY

1. Humoral immunity deficiency

2. Cellular immunity deficiency
3. Phagocytic cell defects
4. Complement deficiency
 HUMORAL IMMUNODEFICIENCY

• Humoral immunodeficiency refers to diseases resulting from impaired

antibody production because of either a molecular defect intrinsic to B
cells or a failure of interactions between B and T cells

• Presentation: recurrent, often severe, upper and lower respiratory tract

infections with encapsulated bacteria (eg, Streptococcus
pneumoniae, Haemophilus influenzae). Children commonly present with
recurrent otitis media, sinusitis, and pneumonia
 LABORATORY TESTS

Type Initial tests Additional tests

Humoral Immunity IgG, IgM, IgA and IgE B cell phenotyping and
Deficiency levels flow cytometry (CD19,
CD 20)
Antibody function test:
Specific antibody titers to Flow cytometry for
protein (eg, tetanus, CD40 ligand
diphtheria) and
polysaccharide (eg, BTK gene mutation
pneumococcal
polysaccharides, H.
influenzae type B capsular
polysaccharide) antigens
 CAUSES OF HUMORAL
IMMUNODEFICIENCY

I. Defects in B cell X-linked agammaglobulinaemia

development - Caused by defect in the bruton tyrosine (Btk) involved in
the B cell signal transduction pathway, leading to arrest in b
cell differentiation at the pre-B cell stage

I. Class switch CD40L deficiency

recombination defects - Failure of class switch from IgM to IgA and IgG, resulting in
normal or high IgM but low IgG, IgA and IgE

I. Common variable Typically presents in adolescence

immunodeficiencies
(CVID) Impaired vaccine response
 CELLULAR IMMUNODEFICIENCY

• Defects in cellular immunity — Specific cellular immunity is mediated by T

cells, and defects affecting these T cells underlie the most severe
immunodeficiencies. However, because antibody production by B cells
requires intact T cell function, most T cell defects lead to combined
(cellular and humoral) immunodeficiency.

• Presentation: persistent lymphophenia, recurrent bronchiolitic disease, oral

candidiasis, diarrhea, poor weight gain in a young infant – SCID , recurrent
bacterial pneumonia, fungal or viral infections
 LABORATORY TESTS

Type Initial tests Additional tests

Cellular Lymphopenia on FBC T cell phenotyping and
Immunodeficiency subsets (CD3, CD4, CD*,
HIV test CD19, CD 20, CD56)

CXR – looking for absent In vitro T cell

Thymus proliferation to mitogens
 PHAGOCYTIC CELL DEFECTS

• Neutrophil defects can be caused by:

1. Reduced number of circulating neutrophils
2. Defective chemotaxis
3. Defective intracellular killing

• Presentation: Staph. Aureus and gram negative bacteria infections, fungal

infections, Chronic granulomatous disease, recurrent infections with
Aspergillus, Nocarida
 LABORATORY TESTS

Type Initial tests Additional tests

Phagocytic Defects Neutropenia on FBC Nitroblue tetrazolium
(NBT) – measures flow
cytometric oxidative
burst

Flow cytometry for

CD18 and CD15
 COMPLEMENT DEFICIENCY

• Presentation:
• Pyogenic infections caused by encapsulated bacteria
• Autoimmunity (Mainly SLE, glomerulonephritis)
• Hereditary angioedema
 LABORATORY TESTS

Type Initial tests Additional tests

Complement Deficiency C3, C4 level Alternative pathway
assays
CH50 activity (for total
activity of the classical Specific component
pathway) assays
 QUIZ

• Scenario 1
• A 6 month old male child presents with chronic diarrhea,
failure to thrive and disseminated Cytomegalovirus sepsis
• Most likely type of PID?
• Scenario 1
• Answer: Severe Combined Immunodeficiency (SCID)
• Learning points:
• Age of onset gives a clue:
• Onset before 6 months suggests T cell defect (as maternal antibodies are protective
prior to that)
• Onset between 6-12 months suggests combined B and T cell defects (as maternal
antibodies disappear around 6 months of age)
• Onset later in life suggests B cell defect or secondary immunodeficiency
• X-linked SCID is the most common form of SCID (child is a boy)
 QUIZ

• Scenario 2
• 10 year old boy with giardiasis, immune thrombocytopic purpura,
recurrent sinopulmonary infections complicated by bronchiectasis,
also has splenomegaly and lymphoid hyperplasia of gastrointestinal
tract.
• Type of PID?
• Scenario 2

• Answer: Common Variable Immunodeficiency (CVID)

• Clinically heterogenous with wide range of presentation and severity
• Presents in adolescents and early adulthood
• 4 main groups of clinical manifestations: Infections (bacterial sinopulmonary
infections, gastroenteritis – Giardia, Campylobacter, Severe VZV infection, PCP),
Autoimmunity (AIHA, ITP, Crohn’s disease), Granulomatous disease, non-
malignant lymphoproliferative disease
 QUIZ

• Scenario 3

• 5 year old girl with recurrent Neisseria meningitis. Full

blood count was normal, immunoglobulin levels normal.
• Type of PID?
• Scenario 3

• Would suspect a complement deficiency in this case as

FBC and Immunoglobulin screen are normal
• Infections with encapsulated bacteria Neisseria species
are common presentations of complement deficiencies
 LEARNING POINTS

• Knowing when to suspect Primary Immunodeficiencies and

when to test for them
• Understanding the difference in innate vs adaptive
immunity and the typical presentations in the different
types of PID
• Basic interpretation of immunodeficiency work up and
tests