Immune deficiency disorders have been grouped as disorders of:

- B lymphocytes

- T lymphocytes

- B and T lymphocytes

- phagocytic cells

- complement

Primary immune deficiency disorders - rare

- may be hereditary or acquired

- the deficiency is the cause of the disease

- there are >80 recognized syndromes

Secondary immune deficiency disorders - common

- the deficiency is the result of an underlying disease or other factor

- only in males; no mature B cells
- defective B cell tyrosine kinase gene (btk gene, X-LA gene, Brutonʼs tk gene)
- dramatically decreased immunoglobulin levels - all 5 isotypes
- small or absent tonsils and lymph nodes (major diagnostic findings)
- many infections after 6-9 months of age: Haemophilus influenzae, Strep. pneumoniae

- treatment:  antibiotics, pooled IgG

- is a delay in the ability of B cells to produce IgG
- low IgG (levels of other isotypes are usually normal)
- appears to be due to lack of help from CD4+ T helper (Th) cells
- may persist for up to 36 months; resolves spontaneously

- treatment usually not given (except antibiotics, if needed)

- is acquired; onset of symptoms occurs most often at 15-35 years of age
- B cells are present, but they do not differentiate into mature B cells

(plasmacytes): (1) neither divide nor secrete antibody (2) do divide, but still do not secrete antibody
- one or more of the three major isotypes (IgG, IgA, IgM) is deficient
- decline in T cell function may occur with time in relatively high % of patients
- cause(s) unknown (B cells do not receive proper signals from CD4+ Th cells?)
- high frequency of autoimmune disease and malignancy
- frequent infections (similar to Bruton's disease)

- treatment: antibiotics, pooled IgG (similar to Brutonʼs disease)

- most common antibody deficiency
- seen in 1/700; 1/200 if allergic
- cause(s) unknown
- failure in terminal differentiation of IgA-producing B cells
- recurrent sinopulmonary infections and chronic diarrhea are common
- autoimmune disease is common (~50%)
- overall prognosis is good

- treatment:  antibiotics

Selective Immunoglobulin Deficiencies:

IgA deficiency

- variable degree of deficiency
- caused by an "interference" in the development of pharyngeal pouches (3 & 4)
- "no" T cells, "no" thymus
- "no" parathyroid gland – hypocalcemia (tetany, seizures)
- facial (eyes, ears, cleft lip/palate, etc.), heart and blood vessel malformations 
- great majority (~90%) have learning disabilities
- frequent infections: Candida albicans, Pneumocystis jirovecii (old name: P.  carinii), viral infections (live vaccines) can be fatal

- treatment:  transplantation of fetal thymus, cardiac surgery, Ca supplement, antibiotics

- chronic infection of skin and mucus membranes with Candida (esp. C. albicans)
- involves a selective T cell defect (possibly inherited) - varies in severity
- normal T cell response to infectious agents other than Candida
- normal B cell response to all infectious agents

- treatment:  antifungal drugs

- known as a “Bubble Boy” disease due to defective lymphoid stem cells; therefore "no" T or B cells (some patients also have virtually “no” NK cells and/or “no” other leukocyte types)

- extreme susceptibility to all infectious agents
- live vaccines can be rapidly fatal
- skin rash is common

- defective gene on X chromosome that codes for γ chain of IL-2 receptor (most common); this γ chain also forms part of the receptors for IL-4, 7, 11,15, 21; lymphoid stem cells do not receive appropriate growth and maturation signals

- treatment:  bone marrow transplant, ADA enzyme injections (ADA gene therapy)

- very complex disorder, poorly understood; broad spectrum of immunological defects
- due to mutations in gene encoding WASP (Wiskott-Aldrich Syndrome Protein)
- IgM level is low (high catabolism rate); high IgA (IgE may also be high)
- T cell count in children may be normal, but declines with time; low protection
- thrombocytopenia, abnormal platelets, bleeding, and eczema are also present

-  treatment: antibiotics, antiviral drugs, topical steroids for eczema, platelet transfusion, bone marrow transplant

- relatively slowly progressive disease
- defective ATM (ataxia telangiectasia mutated) gene that assists in DNA repair
- defective repair of DNA damage results in mutations in:

• T cell antigen receptor (TCR) genes
• Heavy (H) chain genes of antibody

- IgA is low more often than other isotypes
- high incidence of lymphoma/leukemia; high susceptibility to radiation
- severe cerebellar ataxia (muscle incoordination); later other neurological abnormalities (eye twitching, speech and swallowing difficulty)
- "spider-like" enlargement of blood vessels

- treatment:  supportive care, pooled IgG (if deficient)

- neutrophils, monocytes, macrophages are deficient
- mutations in genes associated primarily with NADPH oxidase activity
- deficiency in NADPH oxidase (critical in oxidative burst)

NADPH  +  2O₂ ------> NADP⁺  +  2O₂^-  +  H⁺

- results in granulomatous abscesses, especially in lymph nodes, lungs and liver
- greatly increased susceptibility to bacterial and fungal infections

- treatment:  broad-spectrum antibiotics, antifungal drugs, abscess drainage, bone marrow transplant, Interferon-γ1b for prevention of infection (approved by
FDA for CGD) NADPH oxidase

- neutrophils, monocytes, macrophages are deficient
- mutated LYST (lysosomal trafficking regulator gene) gene; digestive enzymes fail to enter lysosomes
- low level of enzymes in large granules
- killing by phagocytic cells is delayed
- low killing by NK and T cytotoxic cells is also possible
- characterized by infections (esp. bacteria), partial oculocutaneous albinism; extreme
photophobia, rapid involuntary eye movements and other CNS abnormalities 

- treatment:  antibiotics, bone marrow transplant

- C1-inhibitor (also known as C1-esterase inhibitor) deficiency
 

- C1-inhibitor inhibits:  C1qrs activation factor XII and kallikrein (coagulation cascade)

- results in increased vascular permeability        
- recurrent attacks of swelling, especially skin and mucus membranes
intestinal swelling may cause cramps, nausea, vomiting, diarrhea; swelling of larynx may be fatal
- attacks can be induced by trauma, menses, violent exercise, extremes of temperature and anxiety
- no increase in infections

- no specific treatment (laryngeal edema – tracheotomy)
- prophylaxis:  C1-inhibitor (FDA approved in 2008), attenuated androgens, anabolic
steroids

- very rare
- can be in one or more subclasses
- Low IgG2 +/- IgG4 occurs most often in children
- Low IgG3 occurs most often in adults
- failure in terminal differentiation of IgG subclass-producing B cells
- recurrent bacterial infections are common (ear, sinusitis, bronchitis)

- treatment:  antibiotics, pooled IgG

Selective Immunoglobulin Deficiencies:

IgG Subclass Deficiency

- B cells cannot switch from IgM to production of other isotypes (especially IgG, IgA and IgE; IgD is usually OK)
- some cases are related to mutated or deficient CD40-mediated T/B cell signaling
- high IgM; most other isotypes are low or absent
- IgM-producing plasmacytes infiltrate tissues (especially GI tract)
- high rate of liver abnormalities, including liver cancer
- IgM autoantibodies may appear (anti-neutrophil, anti-RBC, etc.)

- treatment:  antibiotics, pooled IgG

Selective Immunoglobulin Deficiencies:

Immunodeficiency with High IgM (HIGM)

- known as a “Bubble Boy” disease due to defective lymphoid stem cells; therefore "no" T or B cells (some patients also have virtually “no” NK cells and/or “no” other leukocyte types)

- extreme susceptibility to all infectious agents
- live vaccines can be rapidly fatal
- skin rash is common

 -ATP and dATP accumulate to toxic levels in lymphoid stem cells 

- treatment:  bone marrow transplant, ADA enzyme injections (ADA gene therapy)

- known as a “Bubble Boy” disease due to defective lymphoid stem cells; therefore "no" T or B cells (some patients also have virtually “no” NK cells and/or “no” other leukocyte types)

 - extreme susceptibility to all infectious agents
- live vaccines can be rapidly fatal
- skin rash is common

-lack of HLA class I, II or I & II
-mutations are in genes that code for a transporter protein (class I), proteins that function in transcription (class II) or both 

- treatment:  bone marrow transplant, ADA enzyme injections (ADA gene therapy)

- known as a “Bubble Boy” disease due to defective lymphoid stem cells; therefore "no" T or B cells (some patients also have virtually “no” NK cells and/or “no” other leukocyte types)

- extreme susceptibility to all infectious agents
- live vaccines can be rapidly fatal
- skin rash is common

 - most severe form of SCID; rare disease due to
-developmental arrest of precursor cells at a very early stage;
-lymphocytes, granulocytes, monocytes are deficient; -death within a few weeks (maximum)

- treatment:  bone marrow transplant, ADA enzyme injections (ADA gene therapy)

Early (C1, C2, C4) complement component deficiencies - high incidence of autoimmune disease

C3 deficiency - increased incidence of autoimmune disease - increased susceptibility to bacterial infections

Late (C5, C6, C7, C8, C9) complement component deficiencies
- Infections with Neisseria meningitides, other Neisseria species and other Gram-negative bacteria (most common type of infection when deficiency in C3, C5-9 exists)

Human Immunodeficiency Virus Type-1 (AIDS)

-infects CD4+ cells