Immunodeficiency & Immunoproliferative Disorders

the absence of or impaired function of T cells or B cells in the immune system

What is cellular immunodeficiency?

• DiGeorge Syndrome

• Severe Combined Immunodeficiency (SCID)

• Chronic Mucocutaneous Candidiasis

• Ataxia Telangiectasia

• Wiskott-Aldrich Syndrome (WAS)

• Bruton X-Linked Agammaglobulinemia

• Common Variable Immunodeficiency (CVID)

• Hyperimmunoglobulin M Syndrome

• Hyperimmunoglobulin E Syndrome (HIES)

  • aka Job Syndrome

List the 9 immunodeficiency disorders in this lecture

• DiGeorge Syndrome

• Severe Combined Immunodeficiency (SCID)

  • both T cell and B cell def

• Chronic Mucocutaneous Candidiasis

• Ataxia Telangiectasia

• Wiskott-Aldrich Syndrome (WAS)

• Hyperimmunoglobulin E Syndrome (HIES)

  • both T cell and B cell def

Of the 9 immunodeficiencies in this unit, which ones are T cell deficiencies?

• Severe Combined Immunodeficiency (SCID)

  • both T cell and B cell def

• Bruton X-Linked Agammaglobulinemia

• Common Variable Immunodeficiency (CVID)

• Hyperimmunoglobulin M Syndrome

• Hyperimmunoglobulin E Syndrome

  • both T cell and B cell def

Of the 9 immunodeficiencies in this unit, which ones are B cell/antibody synthesis deficiencies?

• a T cell deficit caused by chromosome deletions

• congenital, severity varies

• classic triad of features:

  • cardiac anomalies, hypoplastic thymus, and hypocalcemia (due to underdeveloped parathyroid gland)

  • cleft lip and palate is also common

  • pharyngeal pouch syndrome

• types:

  • partial - hypoplastic thymus

  • complete - athymic

    • life expectancy for infants who don’t undergo thymus transplantation is < 1 year

What is DiGeorge Syndrome?

• a disorder caused by mutations in several genes

  • genes responsible for T cell function, B cell development, and NK cells

• can be autosomal recessive, but X-linked is most common

• causes: recurrent and severe infections, chronic diarrhea, failure to thrive, and opportunistic infections

• usually fatal within one year if T cell immunity is not corrected

• 90% survival rate with hematopoietic cell transplantation (HCT)

What is Severe Combined Immunodeficiency (SCID)?

• T cell defect that causes failure to recognize Candida albicans

• chronic or recurrent Candida infections of the oral cavity, nails, and skin

  • can happen in the esophagus, GI tract, or vagina

• endocrine problems, such as hypoparathyroidism or hypocalcemia, can result

• biggest threat is adrenal failure

What is Chronic Mucocutaneous Candidiasis?

• rare, inherited neurodegenerative disease resulting from a defect in the ATM gene

  • responsible for T cell deficiency and DNA repair

• affects the brain, spinal cord, and immune system

  • unsteady walking, lack of balance, slurred speech, difficulty swallowing, unintentional movements, etc.

  • red spider veins around the eyes

• can also cause chronic respiratory infections

  • due to a lack of secretory IgA, IgG and IgE may also be decreased

• individuals are more susceptible to cancer

  • bc of the inability to repair DNA

What is Ataxia Telangiectasia?

• presence of a defective gene that codes for WASp, which affects cell adhesion and migration

• X-linked, only affects males

• causes immune insufficiency and bleeding

• manifests as:

  • thrombocytopenia purpura, eczema or atopic dermatitis, or recurrent bacterial, viral, and fungal infections

• decreased T cells

• increased IgA and IgE, decreased IgM

• increased risk of malignancies (15-20% of patients will develop)

What is Wiskott-Aldrich Syndrome (WAS)?

• a mutation of the gene that codes for Bruton tyrosine kinase

• B cell development is halted (cells remain in the pre-B cell phase)

• B cell populations are absent, therefore immunoglobulins are decreased or absent as well

• T cells are normal or increased

• primarily happens in young boys

• bacterial infections are common

What is Bruton X-Linked Agammaglobulinemia?

• a group of disorders caused by defective antibody synthesis

  • decreased concentration of immunoglobulins, near absence of IgA

• T helper cells are either absent or dysfunctional, and there’s an excess of T suppressor cells

• B cells don’t differentiate into plasma cells

• symptoms:

  • frequent sinus and pulmonary infections, diarrhea, endocrine and autoimmune disorders, and giardiasis

• typically manifests around 30-40 years old

What is Common Variable Immunodeficiency (CVID)?

• an X-linked gene abnormality

• causes febrile infections

  • otitis, sinusitis, pneumonia, and tonsilitis

• causes hematological problems

  • neutropenia (can be transient, cyclic, or persistent)

  • thrombocytopenia

  • hemolytic anemia

• greatly elevated IgM, decreased IgA and IgG

• individuals are usually symptomatic before 2 years old

What is Hyperimmunoglobulin M Syndrome?

• rare autosomal dominant gene mutation affecting multiple genes

  • neutrophils have impaired chemotaxis

  • T cells have impaired development into T helpers

  • reduced memory B cells

• causes recurrent, severe staphylococcal abscesses of the skin, joints, and lungs

• presents in infancy

• treatment

  • hematopoietic stem cell transplant (HCT)

  • gene therapy

  • enzyme replacement

  • immunoglobulin replacement

What is Hyperimmunoglobulin E Syndrome/Job’s Syndrome?

a nonspecific term that refers to diseases or disorders of the blood (ex: plasma cell dyscrasia)

What is dyscrasia?

a dysproteinemia in which the level of a single type of antibody is increased

In general what is a monoclonal gammopathy?

a dysproteinemia in which the level of multiple types of antibodies are increased

In general, what is a polyclonal gammopathy?

• monoclonal gammopathy

  • originates from a single clone of plasma cells that synthesize elevated levels of a single Ig class (known as monoclonal proteins)

  • can be benign or malignant

  • includes multiple myeloma and waldenstrom macroglobulinemia

• polyclonal gammopathy

  • involves multiple clones of plasma cells that produces multiple Ig classes

  • consists of one or more heavy chains and both light chain types

  • seen in chronic infection or inflammation

    • chronic liver disease or chronic hepatitis

What are the 2 types of plasma cell dyscrasias?

• used to separate proteins in patient serum for identification

• multiple myeloma can be detected

What is serum protein electrophoresis used for in the lab?

• a plasma cell malignancy of the bone marrow

  • BM is 90% plasma cells

• most common cause of dysproteinemia

• possible causes

  • radiation, viral infection, asbestos, benzene

• bence-jones proteins in the urine

• causes bone pain, anemia, renal insufficiency, and recurrent infections

• fatalities occur as a result of renal failure

  • 1-3 years after diagnosis

• onset is 40-70 years old

What is multiple myeloma?

• a malignant lymphocyte and plasma cell proliferation disorder

• causes abnormally high levels of IgM

• possible causes

  • genetics, post-infection Hep B, Rocky Mountain Spotted Fever, or autoimmune disorders

• onset is 60-64, progresses slowly

• cryoglobulins present in serum

• symptoms:

  • weakness, fatigue, headaches, and weight loss

• causes hyperviscosity syndrome

  • leads to congestive heart failure, headache, dizziness, loss of visual acuity, bleeding, and anemia

What is Waldenstrom Primary Macroglobulinemia?

• a monoclonal protein disorder with no features of MM or related disorders

• can develop into a malignant monoclonal gammopathy

• characteristics:

  • serum monoclonal protein concentration: < 3 g/dL

  • < 10% plasma cells in the BM

  • absence of lytic bone lesions (as opposed to MM)

  • anemia, hypercalcemia, and renal insufficiency

What is Monoclonal Gammopathy of Undetermined Significance (MGUS)?

• LCD

  • disorder where only kappa or lambda monoclonal light chains are produced (known as bence jones proteins)

  • makes up 10%-15% of monoclonal gammopathies

• HCD

  • presence of the heavy chain component of Ig molecules

  • alpha HCD: most common, seen in Mediterranean men

  • gamma HCD: Franklin Disease

  • Mu HCD is rare

Describe light chain disease and heavy chain disease