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Chapter 28: Immune Deficiency, Immune Deficiency disorders

January 19, 2021Elementary Immunology

IMMUNE DEFICIENCY

Definition:

  1. Immune Deficiency is a failure in the immune system to perform the normal function.
  2. OR Clinically relevant illness resulting from a defect or deficiency in one or more immune system components, which may be congenital (primary) or acquired (secondary).
  3. Immune deficiency disorders may be caused by a defect in the quality or quantity of lymphocytes, which may be congenital or acquired.
  4. This may be combined disorders of B and T lymphocytes or either T lymphocytes or B lymphocytes.
  5. Immune deficiency disorders reflect an impairment in the mechanism of immunity  like:
      1. The defensive  part of the body like:
        1. Skin.
        2. Respiratory mucosa and its lining.
        3. GIT mucosa and lining.
      2. Defective phagocytosis and inflammatory response, including complement and other biological components.
      3. Cell-mediated delayed hypersensitivity reaction.
      4. The major congenital or inherited causes are rare.
  6. B-lymphocytes defect (deficiency):
    1. B-L defect appears after 6 months of the age, that period is covered by the maternal antibodies.
    2. Defective B-L function is characterized by a recurrent bacterial infection like the sinopulmonary area:
      1. Staphylococcal.
      2. Streptococci.
      3. Hemophilus.
    3. Intestinal infestation with G lamblia.
    4. Opportunistic infections are common by fungi and viruses.
  7. T-lymphocytes  defect (deficiency):
    1. T-L deficiency patients are susceptible to viral, fungal, and protozoal infections.
    2. These diseases present at an early age often in the neonatal period.
    3. These cases are often associated with B-L deficiency to a certain level.
  8. Severe combined immunodeficiency (SCID):
    1. This is a syndrome characterized by decreased or absent T-L function, low or undetectable immunoglobulins level, and thymic dysplasia.
    2. This will lead to life-threatening immunodeficiency that is only treated by bone marrow transplantation.
    3. This disease is due to genetic abnormalities like:
      1. 50% of the cases are X-linked recessive and due to defects in the IL-2.
      2. Rest 40% of the cases are autosomal recessive and are due to an enzyme deficiency of adenosine deaminase.
      3. The third is JAK3 deficiency, purine nucleoside phosphorylase, CD3 deficiency, and RAG1/RAG2 deficiency.

B-L and T-L disorders:

B-L diseases T-L diseases
Congenital causes Congenital causes
Bruton’s agammaglobulinemia DiGeorge’s  syndrome  (Thymic hypoplasia)
Acquired causes Acquired causes
  1. Autoimmune diseases
  2. Multiple myeloma
  1. Acquired immune deficiency syndrome (AIDS)
  2. Systemic lupus erythematosus
  3. Chronic lymphocytic leukemia
  4. Hodgkin’s disease

The immunodeficiency may be:

  1. Primary: Due to a defect in congenital or genetic abnormality.
  2. Secondary: More common and is due to other conditions or therapy like steroids or immunosuppressive therapy.

Deficiency diseases of B and T lymphocytes (Primary/secondary immune deficiency diseases):

Clinical manifestations Deficiency of B-lymphocytes Deficiency of T- lymphocytes Deficiency of both B and T -lymphocytes
Congenital causes
Bruton’s agammaglobulinemia
  1. Bruton’s agammaglobulinemia:
  2. Recurrent pyogenic infection
  3. More common in males
  4. Starts after the age of 6 months.
  5. Ultimately patients will end up in bronchiectasis
  6. Serum IgG level is markedly low
  7. Normal immunity for fungal and viral infections
  8. But are susceptible to polio, hepatitis, and enteroviruses
  9. Increased incidence of leukemia, lymphoma, and autoimmune disease
Autoimmune diseases B lymphocytes
Multiple myeloma B lymphocytes
Secondary causes
AID’s T lymphocytes
Chronic lymphocytic leukemia T lymphocytes
Hodgkin’s lymphoma T lymphocytes
Chronic mucocutaneuos candidiasis
  1. Chronic mucocutaneuos candidiasis
  2.  Selective defect in T-L
  3. There is a chronic  mucocutaneous candidal infection
  4. Resistant to treatment
  5. These patients may be associated with endocrinopathies
Genetic abnormality based immunodeficiency diseases
DiGeorge syndrome DiGeorge syndrome

  1. Due to failure of the 3rd and 4th pharyngeal pouch
  2. There are T-L deficiency and thymic hypoplasia
  3. There is hypoplastic parathyroid gland
  4. There are great anomalies of the great vessels
  5. There are typical facies:
    1. Low set ears
    2. Hypertelorism
    3. Mandibular hypoplasia
    4. Bifid uvula
    5. Esophageal atresia is common
Wiskott-Aldrich syndrome
  1. Wiskott-Aldrich syndrome
  2. This is an X-linked disease
  3. Characterized by a triad of:
    1. Eczema
    2. Thrombocytopenia
    3. immune deficiency is due to both T and B-lymphocyte
    4. There is the loss of CD43 antigen on the circulating leukocytes and platelets
    5. These patients have increased susceptibility to pneumococci, encapsulated bacteria, pneumocystis carinii, and herpes virus
    6. 12% increased chances for malignancies
Ataxia-telangiectasia (Louis-Bar syndrome)
  1. Ataxia-telangiectasia (Louis-Bar syndrome)
  2. This is an autosomal-recessive disease caused by the mutation in the ATM gene on 11q22.3
  3. Combined immunodeficiency of B and T lymphocytes
  4. IgA is usually deficient.
  5. Impaired response to pneumococcal vaccine.
  6. Characterized by the:
    1. Cerebellar ataxia
    2. Oculocutaneous telangiectasia
    3. Recurrent sinopulmonary infections
    4. Increased incidence of malignancies
    5. MRI shows usually small cerebellum.
    6. Increased level of AFP and CEA
    7. The lifetime risk for malignancy is 38%
Duncan disease (X-linked lymphoproliferative disease)
  1. Duncan disease
  2. X-linked lymphoproliferative disease
  3. These patients have a common variable immune deficiency-like syndrome  defect, manifesting:
    1. Hypogammaglobulonemia
    2. With or without a decrease in the number of B-L, T-L, or NK cells subset.
  4. There is the fulminant and often fatal outcome with Epstein-Barr virus infection
  5. There may be a neoplastic proliferation of the B-L or hepatic failure
  6. CD4:CD8 ratio is inverted in the peripheral blood
  7. the median survival is 10 year
B-L various deficiencies
  1. X-linked infantile agammaglobulinemia
  2. X-linked immunodeficiency with hyper-IgM
  3. selective IgA deficiency
  4. Selective IgM deficiency

Primary immune deficiency diseases are:

B-lymphocytes related diseases:

  1. Selective IgA deficiency diseases associated with:
    1. Allergy.
    2. Autoimmune diseases.
    3. Gastrointestinal diseases.
    4. Central nervous system diseases.
    5. Pulmonary infections.
    6. Malignancy.
  2. Selective IgM deficiency.
  3. IgG subclasses deficiency.
  4. X-linked infantile aggamaglobulinmeia.
  5. X-linked immunodeficiency with hyper-IgM
  6. Common variable hypogammaglobulinemia

T-lymphocytes related diseases:

  1. Thymoma.
  2. DiGeorge’s syndrome.
  3. Ataxia telengiactasia.
  4. Wiskott-Aldrich syndrome.
  5. Chronic mucocutaneous candidiasis.
  6. Leukocytes adhesion deficiency.
  7. Combined immune deficiency:
    1. Swiss-type.
    2. Thymic alymphophasia.
    3. Adenosine deaminase deficiency.
    4. Nezelof syndrome.

Complement deficiencies related diseases:

These are mostly congenital in origin. These patients are more susceptible to recurrent infections.

Complement deficient Associated diseases
C1 (C1r and C1q) Gram-positive infection mainly in the respiratory system
C2 Gram-positive recurrent infections:

  1. Respiratory system
  2. Meningitis
  3. Tuberculosis
  4. Sepsis
C3 Recurrent gram-positive infections
C4
  1. Gram-positive infection
  2. Sepsis
  3. Meningitis
C5
  1. Meningitis (N.meningitis)
  2. Disseminated gonococcal infection
C6
  1. Meningitis (N.meningitis)
  2. Disseminated gonococcal infection
C7
  1. Meningitis (N.meningitis)
C8
  1. Meningitis (N.meningitis)
  2. Disseminated gonococcal infection
C9
  1. Meningitis (N.meningitis)

Secondary causes of immune deficiency diseases:

  1. Hematological and lymphoproliferative diseases:
    1. Leukemias.
    2. Hodgkin’s lymphoma.
    3. Multiple myeloma.
    4. Sickle cell disease.
    5. Aplastic anemia.
    6. Agranulocytosis.
  2. Viral infections:
    1. Acquired immune deficiency syndrome (AIDS).
  3. Immunosuppressive drugs:
    1. Corticosteroids.
    2. Radiation.
    3. Antimetabolites
  4. Metabolic and other systemic diseases:
    1. Diabetes mellitus.
    2. Malnutrition.
    3. Aging.
    4. Nephrotic syndrome.
    5. Renal failure (uremia).
    6. Protein-losing enteropathy.
    7. Liver diseases.
  5. Surgical procedure:
    1. Splenectomy.
  6. Surgical procedure:
    1. In case of burns.

Classification of immune deficiency:

It is preferable to classify the immune deficiency state according to the immune system’s component rather than classify it as primary or secondary. 

Immune Component deficiency
Diseases
 T-lymphocytes Deficiency
  1.  Third & fourth pharyngeal syndrome (Di-George Anomaly)
  2. Acquired immune deficiency syndrome (AIDS)
  3. Chronic mucocutaneous candidiasis
  4. Thymoma
 B-lymphocytes Deficiency
  1. X-linked Agammaglobulinemia (Bruton’s Syndrome)
  2. Selective IgA deficiency
  3. . IgG subclass deficiency
  4. Common variable immune deficiency
  5. Transient hypogammaglobulinemia of infancy
  6. Selective IgM deficiency
 Combined B and T-cells Defect
  1.  Severe combined immunodeficiency (There are various types in this group)
  2. Wiskott-Aldrich Syndrome
  3. Ataxia telangiectasia
 Neutrophil Defect
  1. Chronic granulomatous disease
  2. Leukocytes adhesion deficiency
 Complement Deficiency
    1. Deficiency of the classical pathway
    2. Deficiency of alternative pathway
    3.  Deficiency of common pathway
    4. Deficiency of regulatory proteins
 Phagocytic NK Cells Chronic granulomatous diseases

Table XXVI – Immune Deficiency Disease
Diseases caused by the immune deficiency of B and T lymphocytes:

Deficiency of B and T lymphocytes

Deficiency of B and T lymphocytes

Distribution of the immune deficiency diseases:

  1. The most common immune deficiency diseases are due to B-lymphocytes disorders is 50%.
  2. This is followed by severe immune combined deficiency  (SCID) is 23%.
    1. This disorder develops in infants resulting from a lake of both B and T lymphocytes. As a result, there is no formation of immunoglobulins (antibodies).
  3. Disorders of the phagocytic cells are 14%.
  4. While T-lymphocytes deficiency is hardly 7%.
    Immune deficiency diseases distribution

    Immune deficiency diseases distribution

Clinical Features of immunodeficiency diseases:

  1. Immune deficiency may arise at any age, but infections associated with them have several typical features:-
  2. There is often chronic or recurrent infection.
  3. These may resolve only partially with conventional therapy.
  4. Infections are usually severe.
  5. The organisms involved may be unusual.
  6. The chances for opportunistic malignancies are more.

Causes of recurrent infections in immunodeficiency:

a) In B-cells deficiency:-
  1.  Bacterial Otitis media
  2.  Pneumonia

b) T-cells and cell-mediated

deficiency:-

  1. Fungal infections
  2. Protozoal infections
  3. Viral infections

c) Phagocytic cells

deficiency:-

  1. Systemic infections with low virulent bacteria
  2. Superficial skin infections
  3. Pyogenic organism
d) Complement deficiency:-
  1. Pyogenic bacteria

e) T-cells deficiency leading to

opportunistic infections:-

  1. Pneumocystis carinii
  2. CMV
  3. Toxoplasma gondii
  4. Mycobacterium avium
  5. Candida albicans

Table-XVIII – Infection suggesting immune deficiency (Recurrent infection)

Infective microorganisms in various immune deficiency disorders:

Infective Agent B-Lymphocyte (defect)
T-Lymphocyte (defect)
Decrease Phagocytes Deficiency of  C – Classical Pathway Deficiency of C-MAC
Bacteria
  1. H.influenzae
  2. streptococcus penumoniae
  3. Staph. aureus
  1. Staph. Aureus
  2. Staph. Epidermidis
  3. Pseudomonas aeroginosa.
  4. E. Coli
  5. Serratia marcescens.
  1. H. influenzae
  2. Strep. Penumonae
  3. Staph. aureus.
  1. N. Meningitidis
  2. N. Gonorrhea
Viruses
  1. Echoviruses
  1. CMV
  2. H. zoster
Flagellate parasite
  1. G. Lamblia
IntracellularMicro-organism
  1. M. Tuberculosis
  2. M. Avium
Fungus
  1. Candida-albicans
Protozoa
  1. Pneumocystis carinii
  2. Toxoplasma Gondii
  1. Candida albicans
  2. Aspergillus Flavus.

Table XXVII – Pattern of infectious organisms encountered in immune deficiency
Diagnostic Approach

  1. Take detail H/O patient, including family history.
  2. Look for the lymphocytes and other parameters in:
    1. Peripheral blood.
    2. Bone marrow.
    3. Lymph nodes.
    4. Spleen.
    5. Thymus.
    6. Tonsils.
  1. Enumerate B-cells, T-cells, and macrophages.
  2. Look for products by the immune response like:
    1. Ig level.
    2. Complement assay.
  1. Look for immune responsiveness like:-
    1. Mitogenic response.
    2. Specific Ab-response.
    3. Rate of H2O2 productions.
    4. Cytochrome b. content.

Functions of B and T – lymphocytes and their functional tests:

Tests T-lymphocytes B-lymphocytes Phagocytes
Enumeration
  1. CD3+
  2.  CD4+
  3.  CD8
  4. Lymphocytes
  1. CD20+
  2. Ig+  cells
  3. Ig-level
  4. IgG subclass level
Neutrophil count

Assessment of

invitro function

  1. PHA stimulation
  2. Ag-specific stimulation
  3. IL-2 production
  1. NBT tests (Nitroblue Tetrazolium)

Assessment of

in vivo function

  1. Delayed hyper. Reaction to PPD or M. Tuberculosis
  1. Specific Ab level isohaemagglutinins
  2. Anti-E.Coli
  3. antitetanus or
  4. Anti-diphtheria toxin

Table XXVIII – Useful Screening Tests for the Assessment of Immune Function in Diagnosing Immune-Deficiency

Possible References Used
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