Immunodeficiency

disorders

Dr.Kumaran Ganesan
Associate professor, IHSM
1/27/2022 1
 Immunodeficiency disorders

Primary Secondary

Specific Non -specific

1.Humoral 1.Complement
2.Cell- mediated 2.Phagocytosis
3.Both
1/27/2022
2
 Primary Immunodeficiency syndromes

Humoral immunodeficiencies

1. X-linked agammaglobulinaemia
2. Transient hypogammaglobulinaemia of infancy
3. Late onset hypogammaglobulinaemia
4. Selective immunoglobulin deficiencies
5. Immunodeficiency with hyper IgM
6. Transcobalamin deficiency 1/27/2022
3
 Primary Immunodeficiency syndromes

Cell - mediated immunodeficiencies

1. Thymic hypoplasia ( Digeorge’s Syndrome)

2. Chronic mucocutaneous candidiasis
3. Purine nucleoside phosphorylase (PNP) deficiency

1/27/2022
4
 Primary Immunodeficiency syndromes

Combined immunodeficiencies

1. Cellular immunodeficiency with abnormal immunoglobulin synthesis (Nezelof syndrome)

2. Ataxia telangiectasia
3. Wiskott Aldrich syndrome
4. Immunodeficiency with thymoma
5. Immunodeficiency with short limbed dwarfism
6. Episodic lymphopenia with lymphocytotoxin
7. Severe Combined Immunodeficiencies (SCID)

1/27/2022
5
 Primary Immunodeficiency syndromes

Disorders of complement

1. Complement component deficiencies

Systemic lupus erythematosus
recurrent pyogenic infection(C3)
Neisserial infection (C6,C7,C8)

2.Complement inhibitor deficiencies

Hereditary angioneurotic edema (C1 inhibitor)
1/27/2022
6
Primary Immunodeficiency syndromes

Disorders of Phagocytosis

1. Chronic granulomatous disease

2. Myeloperoxidase deficiency
3. Chediak – Higashi syndrome
4. Leucocyte G6PD deficiency
5. Job’s Syndrome
6. Tuftsin deficiency
7. Lazy leukocyte syndrome
8. Hyper IgE syndrome
9. Actin binding protein deficiency
10. Shwachman’s disease
1/27/2022 7
Secondary Immunodeficiency
syndromes

1. AIDS
2. Malignancy
3. Metabolic disorders
4. Cytotoxic drugs
5. Infections – measles
6. Ageing
7. Immunosuppressive drugs
1/27/2022
8
Congenital T cell Immunodeficiency
 DiGeorge syndrome(DGS)

• First described in 1829 , congenital absence of thymus and parathyroid glands reported
by Dr.Amgelo Digeorge in 1965.

• Symptoms associated with defective development of pharyngeal pouch system.

• Most cases caused by heterozygous chromosomal deletion at 22q11.2

• 22qDS is the most prevalent microdeletion syndrome.

 DiGeorge syndrome(DGS) – C/Features
• Conotruncal cardiac anomalies - malformations of the infundibulum (conus arteriosus) and
great arteries (truncus arteriosus) that have abnormal ventriculo-arterial alignments and connections.

• Hypoplastic thymus, Hypocalcemia

• Thymic hypoplasia results in T cell deficits.

• Pathogenesis – Defective development of the third and fourth pharyngeal pouches.

• Majority of cases have identifiable genetic causes.

• Most cases of 22q11.2 deletion syndrome are caused by deletion of small piece of
chromosome 22.
DiGeorge syndrome(DGS) – Clinical manifestation
• Cardiac anomalies : Congenital heart disease – Atrial septal defect (ASD)

• Anamalous face : Dysmorphic facial features – small lower jaw

• Thymus aplasia /Hypoplasia : recurrent infection due to T cell defect

• Cleft palate

• Hypocalcemia – Hypoparathyroidism – Tetany.

• Affected chromosome 22

• Remember - CATCH
 (DGS) – Non immunological clinical findings
• Palatal anomalies Skeletal abnormalities
• Speech delay Renal abnormalties
• Learning disabilities Neurologic
• Cardiac abnormalities Dental
• Development delay
• Opthalmologic abnormalities
• Hypocalcemia
• Psychiatric disorders
DiGeorge syndrome(DGS) – Clinical manifestation
• Cardiac anomalies – 80 % DGS

• Cyanotic heart disease in newborn - Interrupted aortic arch, Truncus arteriosus, Tetralogy of
fallot, Atrial or ventricular septal defects (ASD or VSD).

• Upper half of the body is pink lower half is blue.

• Hypocalcemia – 60%

• underdevelopment of thyroid glands , Tetany or seizure, low calcium , elevated phosphorus

• Hypoplastic thymus – Thymus absent with complete DGS

 DiGeorge syndrome(DGS) – Diagnosis

• Cardiac evaluation & echocardiogram

• Serum calcium and phosphorus

• CBC to evaluate lymphopenia

• Chest X ray – evaluate the absence of thymic shadow

• T &B cell by Fluorescence activated cell sorting (FACS)

• Immunoglobulin level
1/27/2022 17
 Autosomal dominant hyperimmunoglobulin E syndrome
( Job syndrome) AD-HIES
• Syndrome of recurrent staphylococcal abscesses, Sinopulmonary infections and severe
Eczema . 1966.

• Increased serum IgE with syndrome have characteristics facial features and skeletal
findings with recurrent bacterial and fungal infections and dermatitis.

• Most patients with AD-HIES have defect in signal transducer and activator of
transcription 3(STAT 3)encoded on chromosome 17q21.

• STAT 3 mutation – decreased Th17 cells – defect in neutrophil /macrophage requirement.

• Defect in Th 17 function.

• STAT 3 defect leads to impaired T helper cell type 9 differentiation.

 Clinical manifestation - AD-HIES
• Dermatitis and recurrent infections . Sinopulmanory and skin infection .

( Candida & Staph)

• Skin abscesses, Eczema, allergic disease, Cancer, etc

• Facial features – broad nasal base and bridge

• Skeletal and dental abnormalties

• Increased risk of lymphoma

• Vascular abnormalties – Aneurysms

• Coarse Facies , Abscesses, Retained primary teeth, Hyper – IgE, Dermatologic (Eczema)
 Lab diagnosis- AD-HIES
• Increased serum IgE level

• Peripheral eosinophilia

• Identifying genetic defect Eg. STAT 3 mutation by molecular test

• Adult or older children – Staphylococcal pneumonia , recurrent abscesses and chronic

eczema

• Treatment

• Bacterial infections treated with suitable antibiotics.

• Recombinant human interferon gamma - used for lowering IgE level

• Bisphosphonates – increases bone mineral density

 IL-12 Receptor Beta 1 deficiency
• IL-12 is responsible for maturation of T cells to Th cells & production of IFN gamma & TNF alpha by T cells.

• Normally Ag presenting macrophages release IL 12 – TH cells transform to T1 type – release of IFN

gamma to activate macrophages.

• Defective IL-12 receptors : Macrophage cannot be activated by IFN gamma leads to no cytotoxicity in
cells infected with intracellular pathogens. ( Mycobacteria , Salmonella)

• Carriers are clinically healthy with normal IL 12 signaling and IFN gamma production patterns.

• Diagnosis – Decreased IFN gamma

 Chronic mucocutaneous Candidiasis (CMCC)
• Heterogeneous group of syndromes with chronic non invasive Candida infections usually
resistant to topic treatment and absence of invasive fungal infections.

• CMCC is associated with impaired T cell response to candida antigen.

• CMCC caused by pathogenic variant in Autoimmune Regulator Gene (AIRE) and

Signal Transducer And Activator Of Transcription I Gene (STAT I)

• Dysfunction of AIRE is associated with chronic mucocutaneous Candidiasis.

• STAT I dysfunction with oral thrush and skin and nail infection
 Clinical features(CMCC)
• Autoimmune hemolytic anemia, immune thrombocytopenia purpura, autoimmune neutropenia, RA

• bonemarrow failure with Aplastic anemia-.

• Neoplastic diseases – Benign and malignant thymomas.

• Multiple abnormalties in immune system includes abnormal in vitro T cell proliferation to candida
antigen. humoral deficiencies

• Classic triad – Mucocutaneous Candidiasis, Hypoparathyroidism and Adrenal failure

• Patients with severe cutaneous involvement have an increased risk of developing skin cancer.

• Other patients with a progressive decline in immunity are at increased risk of developing chronic
lung disease or overwhelming viral or fungal infections
1/27/2022
24
 Diagnosis(CMCC)
• Diagnosis is usually clinical

• Absent in vitro T-cell proliferation when exposed to Candida antigen

• Absent cutaneous reaction to Candida antigen.

• Culture: Lesions can be scraped and sent for culture .

• HIV testing:

• Endocrine function tests: To rule out associated endocrine disorders

• Chest X-ray: Rule out thymoma

1/27/2022
26
 Immune dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX)

• IPEX is a rare, X-linked immune dysregulatory disorder that typically presents

during infancy with a triad of enteropathy, autoimmune endocrinopathy, and
dermatitis.
• Pathogenesis:

• IPEX is immune dysregulation, resulting in autoimmune disease and allergic inflammation.

• IPEX was previously designated X-linked polyendocrinopathy, immune dysfunction, and

diarrhea (XPID) and X-linked autoimmunity and allergic dysregulation (XLAAD).
Immune dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX)

• Clinical Manifestations:

• 1. Life-threatening chronic diarrhea due to an autoimmune enteropathy

• 2. Autoimmune endocrinopathy (neonatal type 1 diabetes or thyroiditis)

• 3. Dermatitis, usually eczematous

• Autoimmune enteropathy : intractable diarrhea, histologic changes on small intestinal biopsy, failed
response to dietary manipulation that also may present with extra-intestinal manifestations

• autoimmune endocrinopathies occur preferentially in individuals who have inherited certain major
histocompatibility complex (MHC) gene
Immune dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX)
• Diagnosis:

• IPEX should be considered in any male infant presenting with chronic intractable diarrhea with failure to
thrive or infantile onset of type 1 diabetes.

• The presence of dermatitis, autoimmune cytopenia's, or thyroiditis further supports the diagnosis.

• The diagnosis is established by mutational analysis of the FOXP3 gene Low or absent CD4+CD25+
regulatory T cells.

• CBC –Eosinophilia, Cytopenia, IgE & IgA increased.

• Skin biopsy - Lymphocytic infiltration.

• Treatment : Hematopoietic cell transplantation —

HCT is the only curative therapy available to IPEX patients.

Congenital B-cell Immunodeficiencies
&
Combined

1/27/2022 30
 Primary Immunodeficiency syndromes

Humoral immunodeficiencies

1. X-linked agammaglobulinaemia
2. Transient hypogammaglobulinaemia of infancy
3. Late onset hypogammaglobulinaemia
4. Selective immunoglobulin deficiencies
5. Immunodeficiency with hyper IgM
6. Transcobalamin deficiency 1/27/2022
31
• It is X-linked recessive primary humoral immunodeficiency syndrome caused by a mutation in the
B-cell tyrosine kinase (BTK) gene, which results in arrested B cell development and
agammaglobulinema. Patients present with recurrent bacterial infections.

• It is characterized by severe hypogammaglobulinemia, antibody deficiency, and increased

susceptibility to infection.

• Bruton tyrosine kinase gene:

• BTK gene defect → defective Bruton tyrosine kinase expressed in B cells → complete
deficiency of mature B cells.

• leads to decreased production of all classes of immunoglobulins.

1/27/2022
33
 Clinical features:
• Clinical symptoms are generally first noted in male infants between 3 and 18 months of age.

• Mostly Recurrent bacterial respiratory tract infections caused by encapsulated pyogenic bacteria,

• hypogammaglobulinemia/agammaglobulinemia and the near absence of CD19+ B cells

• recurrent and chronic sinopulmonary infections and their sequelae include chronic cough, chronic

rhinitis and postnasal drainage, and digital clubbing .

• Hypoplasia of lymphoid tissue. (reduced cell number, in lymphatic tissue.)

 Diagnosis:
• Family history , clinical history, and physical examination.

• confirmed with molecular studies identifying a mutation in the BTK gene.

• Reduction in all classes and subclasses of serum immunoglobulins and B cells

• Flow cytometry:

• Absent or low levels of B cells (marked by CD19, CD20, and CD21)

• Normal or high T cells

• Treatment : Replacement of immunoglobulin.

• General supportive care includes measures to avoid infection and immunization with killed vaccines.

• require aggressive antibiotic therapy

 Selective immunoglobulin deficiencies
• Selective immunoglobulin A (IgA) deficiency defined as the isolated deficiency of serum IgA .

• Severe IgA deficiency refers to serum levels below 7 mg/dL,

• Partial IgA deficiency refers to serum levels above 7 mg/dL.

Normal serum level : IgA 70–400 mg/dl, IgG 700–1600 mg/dl and IgM 40–230 mg/dl

• IgA exists in two distinct forms:

• Monomeric IgA in serum – IgA interacts with the phagocytic arm of the immune system.

• Dimeric secretory IgA in secretions – This form of IgA is found in saliva, milk, colostrum, tears, and
mucosal secretions from the respiratory tract, genitourinary tract, and prostate.

• It is called secretory IgA important in mucosal immunity.

 Clinical manifestations:
• Mostly asymptomatic.

• Recurrent infections - most often affects sinopulmonary tract like recurrent otitis media, sinusitis &
pneumonia. ( Strep, H.influenza).

• Gastrointestinal —IgA-deficient patients suffer gastrointestinal infections due to Giardia lamblia .

• Autoimmune disorders – occurs in 20-30% cases ( SLE, Graves' disease, RA, myasthenia gravis )

• Reactions to blood products — Patients with severe sIgAD (ie, undetectable serum IgA) can
experience infusion reactions to blood products containing small amounts of IgA .

• To prevent transfusion reactions, IgA-deficient patients must be given washed blood products
without IgA or obtain blood from an IgA deficient donor
 Diagnosis:
• Indications for evaluation

• A child with recurrent otitis media, sinusitis, and/or pneumonia

• An adult with recurrent/chronic sinusitis or pulmonary infections

• Patient of any age with one or more of the following:

• Absence or low level of immunoglobulin A (IgA) .

• Celiac disease Gastrointestinal infection with Giardia lamblia .

• Unexplained and recurrent autoimmune phenomena

• A family history of IgA deficiency or common variable immunodeficiency (CVID)

• A past anaphylactic reaction to blood products

 Common variable immunodeficiency (CVID)
• (CVID) is a heterogeneous disorder involving immune dysfunction of B & T cells & dendritic cells.

• characteristic immunologic defect is the inability of B cells to differentiate into plasma cells capable of
secreting all immunoglobulin types.

• CVID is not a single disease - hypogammaglobulinemia syndromes with many genetic defects.

• Age-specific reduction in serum concentrations of immunoglobulin G (IgG), in combination with low

levels of IgA and/or IgM

• Poor or absent response to immunizations.

• B cells are phenotypically normal but are unable to differentiate into Ig producing cells, resulting in low
immunoglobulins of all classes.
• Infections (94 percent)
Clinical manifestations:(CVID)
• Hematologic or organ-specific autoimmunity (29 percent)

• Chronic lung disease (29 percent)

• Bronchiectasis (11 percent)

• Gastrointestinal inflammatory disease (15 percent)

• Malabsorption (6 percent)

• Granulomatous disease (10 percent)

• Liver disease/hepatitis (9 percent)

• Lymphoma (8 percent)

• Other cancers (7 percent)

 Diagnosis: :(CVID)
• Quantitative immunoglobulin levels : low levels of IgG, IgA, and IgM.

• The diagnosis of common variable immunodeficiency (CVID) can be assigned to a patient over age
four who demonstrates all of the following characteristics:

• Significantly reduced total serum concentrations of immunoglobulin G (IgG)

• Low immunoglobulin A (IgA) and/or immunoglobulin M (IgM)

• Poor or absent response to immunization

• Treatment: Immune globulin replacement therapy.

• The usual initial dosing for IVIG in patients with CVID is 300 to 600 mg/kg every three to four weeks with
or without premedication.
1/27/2022
42
X- linked or autosomal recessive
IgA, IgG Ig M
Recurrent infections and autoimmune processes

Low plasma cells and Ig

1/27/2022
43
 Primary Immunodeficiency syndromes

Combined immunodeficiencies

1. Cellular immunodeficiency with abnormal immunoglobulin synthesis (Nezelof syndrome)

2. Ataxia telangiectasia
3. Wiskott Aldrich syndrome
4. Immunodeficiency with thymoma
5. Immunodeficiency with short limbed dwarfism
6. Episodic lymphopenia with lymphocytotoxin
7. Severe Combined Immunodeficiencies (SCID)
1/27/2022
44
Nezelof syndrome is an autosomal recessive congenital immunodeficiency
condition due to underdevelopment of the thymus.

1/27/2022
45
X linked recessive disease , Signal transduction
defect in platelets and lymphocytes

IgM and IgG levels are decreased &

Increased IgA and IgE levels
1/27/2022
46
 Combined B cell and T cell Immunodeficiency
• Severe combined immunodeficiency syndrome(SCID):

• Presents with recurrent bacterial, viral and fungal infections due to dysfunction of both B and T cells.

• It is X-linked autosomal recessive inheritance.

• The genetic defect is mutation in the common γ-chain subunit of cytokine receptors such as IL-2, IL-4,
IL-7, IL-9, IL-11, IL15, and IL-21. due to deficiency of the enzyme adenosine deaminase.

• Hyper IgM Syndrome:

• patients produce IgM antibodies but fail to produce IgG, IgA, and IgE antibodies

• Recurrent bacterial infections

• IgM antibodies may react with blood cells, there can be autoimmune hemolytic anemia,
thrombocytopenia.
 Combined B cell and T cell Immunodeficiency
• Ataxia-telangiectasia:
• Autosomal-recessive disorder (Due to mutation in ATM gene on chromosome 11)
• Abnormal gait (ataxia) , Vascular malformations(telangiectases)
• Neurologic deficits(cerebellum is involved)
• Increased incidence of tumors .
• Reduced IgE levels and absent IgA
 Primary Immunodeficiency syndromes

Disorders of complement

1. Complement component deficiencies

Systemic lupus erythematosus
recurrent pyogenic infection(C3)
Neisserial infection (C6,C7,C8)

2.Complement inhibitor deficiencies

Hereditary angioneurotic edema (C1 inhibitor)
1/27/2022
49
Primary Immunodeficiency syndromes

Disorders of Phagocytosis

1. Chronic granulomatous disease

2. Myeloperoxidase deficiency
3. Chediak – Higashi syndrome
4. Leucocyte G6PD deficiency
5. Job’s Syndrome
6. Lazy leukocyte syndrome
7. Hyper IgE syndrome
8. Actin binding protein deficiency
9. Tuftsin deficiency
10. Shwachman’s disease
1/27/2022 50
Chronic granulomatous disease (CGD) is a genetic disorder in which white blood

cells called phagocytes are unable to kill certain types of bacteria and fungi.

1/27/2022
51
 rare, inherited, complex, immune disorder that usually
occurs in childhood characterized by reduced pigment in the skin and eyes
(oculocutaneous albinism), immune deficiency with an increased
susceptibility to infections, and a tendency to bruise and bleed easily.

1/27/2022
52
1/27/2022
53
1/27/2022
54
Secondary Immunodeficiency
syndromes

1. AIDS
2. Malignancy
3. Metabolic disorders
4. Cytotoxic drugs
5. Infections – measles
6. Ageing
7. Immunosuppressive drugs
1/27/2022
55
 All are true about severe combined immunodeficiency except:

a. B & T cell deficiency

b. Adenosine deaminase deficiency may occur

c. Affected child can survives beyond adolescence without treatment

d. Can transmit either as X-linked or autosomal recessive defect

e. Person susceptible to recurrent and severe infections

1/27/2022
56
 c. Affected child can survives beyond adolescence without treatment

In Severe Combined Immunodeficiencies (SCID), both CMI are AMI are affected.

It runs as: X linked: Mutation in cytokine receptor

Autosomal recessive: It occurs as: (i) Adenosine deaminase (ADA) deficiency, (ii) Jak3 mutation, (iii)

RAG mutation and (iv) Class II MHC deficiency

The affected infants are susceptible to severe recurrent infections by a wide array of pathogens,

including Candida, Pneumocystis, cytomegalovirus and Pseudomonas.

Prognosis of SCID is poor.

Bone marrow transplantation is the mainstay of treatment.

1/27/2022
57
Thank you