Immunodeficiency Disorders😍

Immunodeficiency Disorders

Disorders of phagocytosis

• Leukocyte adhesion deficiency

• Chediak–Higashi syndrome

• Chronic granulomatous disease

• Tuftsin deficiency

• Cyclic neutropenia

Innate

1. Leukocyte Adhesion Defect (LAD)

• Inheritance:
• All three types autosomal recessive.

Types of LAD:

LAD1

• In LFA-1 integrin (CD 18, CD 11 defective) protein defect on phagocytes
• Leads to impaired migration and
• chemotaxis by C5a, IL-8, leukotriene B4 (LIC)

LAD Type	Defect	Clinical Features / Associations
LAD 1	Beta 2 integrin	Delayed umbilical cord shedding, Recurrent infections NO PUS dysfunctional neutrophils
LAD 2	Sialyl Lewis X (S-LeX) (selectin)	Bombay blood group (no H, A, B antigens; anti-H, anti-A, anti-B Abs) + Delayed umbilical cord shedding Bombay blood group = “Oh”
LAD 3	Kindlin-3 (FERMT3 gene)	Bleeding manifestations

• Mnemonic:
• Bombayil (Bombay blood group) kond povan 2 (LAD 2) pere selct (Selectin) cheyth → SaLu (Sialyl Lewis)
• But Salu nte umbilical cord shed ayilla → kond povan patiilann paranju
• Salu ne kude integrate (Integrin) cheyyan umbilical cord valichu uuri (↓ umbilical cord shedding)
• Apo bleed cheyth → 3 (LAD 3) kinder (Kindlin) joyum ferraro roshe (FERMT 3) yum vangi koduth

2. Chronic Granulomatous Disease (CGD)

• Defect:
• ↓↓ Enzyme NADPH oxidase and PHOX gene
• ↓ Reactive oxygen species (e.g., superoxide)
• ↓ respiratory burst in neutrophils
• Defect in phagocytosis
• NOTE: PHEX gene → Hypophosphatemic Rickets

• Infections:
• ↑↑ catalase-positive infections
• (e.g., Staphylococcus, Klebsiella, Pseudomonas).
• CATALASE positive → Cat in SPACE
• Staphylococcus → Golden color
• Serratio → Red color
• Pseudomonas → Bule green
• Aspergillus
• Candida
• Cryptococcus
• E coli
• Entero bactericea
• M TB
• Micrococcus

• Diagnosis:
• Screening Test: 
• NBT test (Nitroblue Tetrazolium)
• obsolete
• fails to turn blue
• Diagnostic Test: 
• DHR test (Dihydrorhodamine)
• Flow cytometry
• ↓ green fluorescence

• Mnemonic:
• CGD → Caged a Fox (phox) and cat (Catalase) → Nadu (NADPH) nashipiikkan vanna → but Nobody (NBT) drohichu (DHR)

3. Chediak-Higashi Syndrome (CHS)

• Normally, CHSI gene produces LYST

• Defect: 
• Mutation in the CHSI gene
• LYST gene defect 
• (Lysocontsomal transport protein)
• Lysosomal defect.
• No phagocytosis
• Phagolysosome fusion doesn’t happen
• Microtubule

• Mnemonic: CHEDIAC
• CNS problems
• Progressive neurodegeneration
• poor school grades
• Hemorrhage
• Pancytopenia
• Decreased Immunity
• recurrent infections:
• ear/throat, pneumonia
• Albinism
• silvery-gray hair
• Coarse Granules
• Platelet, Neutrophil dense granules

Adaptive

1. Lymphocyte Maturation defect
• Brutons Aggamma
• SCID
• Digeorge

2. Lymphocyte activation and function defect
1. Common Variable Immunodeficiency
2. Hyper IgM
3. Hyper IgE
4. Isolated IgA

3. Systemic disease
1. Ataxia Telengectasia
2. Wiskott-Aldrich syndrome.

Defect in Lymphocyte Maturation

Bruton's Hypogammaglobulinemia

• Mnemonic: Boys (Boys>) are brutal (Bruton) → avare pokkumbo Oops (Opsonisation) n paayum → Buttockil (BTK) adikkum→ because they are not BIG (B cell ↓, IgG ↓)

• Gender: More common in boys

• Gene Defect: BTK gene.

• Defect: B-cell defect.

• BTK gene defect →
1. Immature B cell cannot convert to mature B cell
2. ↑↑ Immature B cell, ↓ Plasma cell, ↓ Immunoglobulins (↓↓IgG)
3. Dysfunctional humoral immunity (↓B cell)
4. Defective opsonisation (↓↓IgG)
5. Recurrent sinopulmonary infection after 6 months of age
• after breastfeeding period

• Immunoglobulins:
• ↓↓ especially IgG → Defective opsonization 
• missing IgG - "garam masala”

Recurrent infections Approach

• Since birth
• T cell defect

• After 6 months
• B cell

• Cladribine, Pentostatin
• ⛔ ADA
• NOTE: SCID
• ADA deficiency

• Lesch Neyhan syndrome
• ⛔ HGPRT

DiGeorge Syndrome:

• 22q11 deletion syndrome

• TBX 1 gene defect

• 3rd > 4th pouch
• fails to develop thymus and inferior parathyroid gland.

• No T lymphocytes

• No PTH → No Ca

• Leads to hypocalcemia and thymic hypoplasia → T cell dysfunction

• CATCH 22 TB
• Cardiac problems (TOF)
• Abnormal faces
• Thymus aplasia/hypoplasia (T-cell problems)
• Cleft lip/palate
• Hypocalcemia (No parathyroid)

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• Chromosome 22q11.2 Deletion syndrome/ Di-George Syndrome /
  Velocardiofacial syndrome (VCFS)
• 30% of these cases may develop schizophrenia.

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Systemic Disease

Ataxia Telangiectasia:

 

Investigations

• ↑ AFP

• ↓ IgA, IgG, and IgE

• Defects in ATM gene
• failure to detect DNA damage
• Failure to halt progression of cell cycle → mutations accumulate

• Mnemonic: Ataxic Telangiectasia Mutation gene (ATM gene)

• AGE (IgA, IgG, IgE) decreases and become fetus (AFP) → Children are ataxic → afraid of Spider (Spider angioma)

• Autosomal Recessive

• Telangiectasia:
• Dilated blood vessels.

• Ataxia:
• Spinocerebellar pathway involved.

• IgA deficiency.

• Increased risk of blood cancer.

• Characterized by:
• Triad:
• cerebellar atrophy (ataxia),
• spider angiomas (telangiectasia A),
• IgA deficiency
• Progressive neurodegeneration
• Immune system dysfunction
• Higher susceptibility to infections
• ↓ Sensitivity to radiation
• limit X-ray exposure
• Lymphopenia
• ↑ Risk of lymphoma and leukemia

Vaccines:

• Generally recommended (for protection)

• Immune response may be impaired (due to underlying immune deficiency)

Wiskott Aldrich Syndrome

 

Findings

Antibodies	Level
IgG & IgM	↓ to normal
IgE and IgA	↑↑↑

• Fewer and smaller platelets

Triad: BIE

1. Bleeding → Thrombocytopenia.

2. Recurrent infections.

3. Eczema.

 

Defect

• X-linked recessive: WASP gene

• MC in males

• Leukocytes and platelets
• unable to reorganize actin cytoskeleton
• defective antigen presentation

• ↑ Risk of autoimmune disease and malignancy

Presentation

• WATER:
• Thrombocytopenia
• Eczema
• Recurrent (pyogenic) infections
• ↑↑ A & E

• Aunty Presented (Antigen Presenting) Whisky to actor (actin cytoskeleton)

Lymphocyte maturation defect

• CAME →
• common variable
• IgA
• IgM
• IgE

Hyper-IgM Syndrome

Defect

• X-linked recessive

Pathogenesis

• Defective CD40L (Most common) on Th cells → Isotope switching defect
• B cell switching from MD to GAE cannot occur → ↑↑ M, ↓↓ AGE

Presentation

• Due to ↓ IgG, A, E
• ↑ Sinopulmonary infections
• Opportunistic infections:
• Pneumocystis,
• Cryptosporidium,
• CMV

• Due to ↑ IgM levels
• Autoimmune thrombocytopenia
• Autoimmune neutropenia
• AIHA

Findings

• Normal or ↑ IgM

• ↓↓ IgG, IgA, IgE

• Failure to make germinal centers

Selective IgA Deficiency

• Defect:
• May be familial or sporadic.
• Most common 1° immunodeficiency.
• May arise 2° to viral infections or medications.

• Presentation:
• Mostly asymptomatic.
• Can see airway & GI infections.
• Autoimmune disease.
• Atopy, anaphylaxis to IgA in blood products.

• Findings:
• ↓ IgA with normal IgG, IgM levels.
• ↑ susceptibility to giardiasis.
• Can cause false-negative celiac disease test & false-positive serum pregnancy test.

Common Variable Immunodeficiency

Defect:

• In conversion/differentiation of mature B cell →
• ↓↓ Plasma cell, ↓ memory cells, ↓ IgE, ↓ humoral immunity

• Cause unknown in most cases.

• ↑ risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections.

Presentation:

• Seen in childhood but usually diagnosed after puberty.

Findings:

• ↑ plasma cells.

• ↑ immunoglobulins.

Miscellaneous

Autoimmune Polyendocrine Syndrome Type 1:

• Negative selection absent
• Controlled by AIRE gene

• Drives expression of self-antigens in the thymus.

• AIRE deficiency →
• Chronic mucocutaneous candidiasis
• Hypoparathyroidism
• Adrenal insufficiency
• Recurrent Candida infections
→ Mnemonic: “Organs in air are affected → adrenal, parathyroid + candida in air will come”

IPEX Syndrome

• T Regulatory cell defect

• X linked

• Cause: FOXP3 deficiency → autoimmunity
• Immune dysregulation
• Polyendocrinopathy
• Enteropathy

• Other Symptoms:
• nail dystrophy, dermatitis

• Seen in male infants, often associated with diabetes.

Chronic Mucocutaneous Candidiasis

• Defect:
• T-cell dysfunction.
• Impaired cell-mediated immunity caused by Candida sp.
• Classic form in AIRE.

• Presentation:
• Persistent noninvasive Candida albicans infections of skin & mucous membranes.

• Findings:
• Absent in vitro T-cell proliferation in response to Candida antigens.
• Absent cutaneous reaction to Candida antigens.

IL-12 Receptor Deficiency

• Defect:
• ↓ Th1 response.
• Autosomal recessive.

• Presentation:
• Disseminated mycobacterial & fungal infections.
• May present after BCG vaccination.

• Findings:
• ↓ IFN-γ.
• Most common cause of Mendelian susceptibility to mycobacterial diseases (MSMD).