Immunodeficiency Disease

A Developmental Approach

Stem cell deficiencies result in combined T and B cell deficiencies.

Deficient T-lymphocyte development results in deficient cell mediated immunity.

Deficient B-lymphocyte development results in antibody deficiency syndromes.

Antibody sequence IgM Þ IgG Þ IgA explains why IgA deficiency is the most frequent antibody deficiency.

Antibody Deficiency Syndromes

X-Linked Agammaglobulinemia of Bruton

X-linked disease seen almost entirely in males
usually does not become apparent until about 6 months of age, when maternal immunoglobulins (Igs) are depleted
characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to differentiate into B cells; as such there are no B cells, plasma cells, or antibody in the blood
block in differentiation is due to mutations in a tyrosine kinase called BTK, needed in process of VDJ rearrangement
patients get recurrent bacterial infections of the respiratory tract (pharyngitis, sinusitis, otitis, bronchitis, and pneumonia)
pathogens responsible almost always Haemophilus influenzae, Streptococus pneumoniae, or Staphylocoocus aureus; all are organisms cleared by phagocytosis for which antibodies are opsinins. Patients are also susceptible to certain viral infections

Hyper IgM Syndrome

Affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies
a T cell disorder in which functionally abnormal T cells fail to induce B cells to make antibodies of isotypes other than IgM
isotype switching normally involves an interaction between the CD40 molecules on B cells and CD40 ligands (CD40L) on activated T cells
in these patients either the CD40 or the CD40L is mutated
patients present with recurrent pyogenic infections because the level of opsonizing IgG antibodies is low

Common Variable Immunodeficiency

Patients have hypogammaglobulinemia (low levels of antibodies), generally affecting all the antibody classes but sometimes only IgG
in contrast to X-linked agammaglobulinemia, most patients have normal or near-normal numbers of B cells in the blood and lymphoid tissues; these B cells, however, are not able to differentiate into plasma cells
Molecular basis of abnormal B-cell differentiation is incompletely understood. Syndromes resemble those seen in X-linked agammaglobulinemia (sinopulmonary pyogenic infections, etc).

Transient Hypogammaglobulinemia of Infancy

Patients have delayed B cell maturation. Though the disease recedes at approximately 12 months of age, after about 6 months of age (when maternal Igs are depleted) patients are vulnerable to pyogenic bacteria (H. Influenzae, S. Aureus, etc).

Deficiencies of cellular immunity (T Cell Defects)

DiGeorge Syndrome (Thymic Hypoplasia)

patients have a variable loss of T cell-mediated immunity due to hypoplasia or lack of the thymus
absence of cell-mediated immunity is reflected in low levels of circulating T lymphocytes and a poor defense against certain fungal and viral infections
plasma cells are present in normal numbers in lymphoid tissues, but lymph nodes and spleen are depleted
immunoglobulin levels may be normal or reduced, depending on the severity of the T-cell deficiency
Patients are in risk for opportunistic infections
Severe cases resemble Severe Combined Immune Deficiency

Therapy: (non-human) fetal thymus extract, epithelium; autologous bone marrow after in-vitro incubation with thymic factors.

Nezelof Syndrome

Severe Combined Immunodeficiency Diseases (SCID)

SCID represents a constellation of genetically distinct syndromes, all having in commin variable defects in both humoral and cell-mediated immune responses (i.e. both B and T cell problems)
Affected infants present with thrush (oral candidiasis), extensive diaper rash, and failure to thrive
Some patients develop a rash shortly after birth owing to transplacental transfer of maternal T cells that cause graft-versus host disease
Forms of disease:

Swiss Type Agammaglobulinemia – defect in the common lymphoid stem cell. Uncommon.

X-linked SCID – genetic defect in several cytokine receptors. As a result lymphoid progenitor cells in patients fail to be stimulated by cytokines. Most common form of SCID (50-60% of cases).

Adenosine Deaminase Deficiency (ADA) – hypothesized that ADA deficiency leads to accumulation of deoxyadenosine and its derivatives (e.g., deoxy-ATP), which are toxic to immature lymphocytes, especially those of T lineage.

Wiskott-Aldrich Syndrome

Abnormalities in platelet maturation, as well as problems with adhesion molecules in both platelets and T cells. Accompanying syndrome is Eczema (skin rash).

Ataxia Telangiectasia

Abnormalities in cellular immunity increase with age. Connected with abnormalities in Cerebellum leading to ataxia.

AIDS

Characterized by defect in CD4⁺ T cell production

Not all AIDS is due to HIV infection (e.g., thymoma with hypogammaglobulinemia), but most is