Immunodeficiency Disorders

Michelle M. Klinek, M.D.

Family Center for Allergy and Asthma

Overview

• Immunodeficiency diseases
  • increase susceptibility to infection, malignancy and autoimmunity
  • may be congenital or acquired (primary or secondary)
  • need to be on alert for presentation at any age

Differential Diagnosis of Infxn

• Hereditary ie Down Syndrome
• Organ System Dysfunction
  • Diabetes -Protein Losing Enteropathy
  • Nephrotic Syndrome -Uremia
• Nutritional Deficiency
  • Protein-calorie malnutrition
• Immunosuppressive agents
  • Radiation - Steroids -Cyclosporine
  • Anticonvulsants

Differential Diagnosis of Infxn

• Infiltrative and Hematologic Diseases
  • Malignancy -Sarcoid
• Surgery and Trauma
  • Burns -Splenectomy
• Primary Immunodeficiency

Epidemiology of Primary Immunodeficiency

• Prevalence of known primary immunodeficiency = 1/100,000, excluding IgA and IgG subclass deficiencies.
  • IgA deficiency 1:500
• More than 50% occur in males due to X-linked inheritance for many disorders.

Distribution of Primary Immunodeficiencies

Adults and Primary Immunodeficiencies

• Primary Immunodeficiencies may present in adults.
  • Some disorders like CVID present later in life ie. 2-3rd decade
  • Mild phenotype may allow initial clinical presentation in adulthood
  • Effective treatment allows survival into adulthood

Immunodeficiency in Adults

Immune Components

• 1. Cell-Mediated - T cells
• 2. Antibody Mediated - B cells
• 3. Phagocytic - PMNs, Mononuclear
• 4. Complement
• 5. Cytokines - communication between cells

Clues

• Infection is the most common clue to immune disorders -Type of infection very helpful
  • Fungi, virus, protozoa, gm(-) intracellular organisms
    • CMI
  • Recurrent meningococcal or gonorrheal infection
    • complement deficiency

Clues

• Bacterial Infections: Otitis Media, Sinusitis, Pneumonia, Meningitis, Diarrhea
  • B cell and Complement disorders, asplenia
• Recurrent Skin Infections: Abscesses
  • Neutropenia, CGD, LAD-1, Hyper IgE
• Infections with Failure to Thrive, Gastroenteritis, Thrush or Atypicals
  • SCIDS, DiGeorge, AIDS, Wiskott-Aldrich

Ontogeny of Immunity

• Pleuripotential stem cell

Innate immune system: phagocytes, antigen presenting cells (dendritic cells, Langerhans), mediators of inflamm - eos, mast , basophils

• Adaptive immune system: Lymphocytes
  • recognize self vs nonself
  • memory, anamnestic response

diversity of the various receptors for ag of the world with diversity of the Tcell receptor and B cell immunoglobulins via gene rearrangement.

Tcells or Cell-Mediated Immunity

• Identified by CD numbers which are markers recognized by monoclonal ab

CD4 - HELPER Bind MHC II proteins with extracellular ag. (bacteria). Helper cells divided into functional sets by cytokines Th1 -DTH, Th2 -allergy (IL-4)

• CD8 CYTOTOXIC Recognize intracellular ag with MHC I proteins and are cytotoxic to virus infected cells and tumors

Tcells

Educated in the thymus where cells that can appropriately respond to an ag in the context of MHC are positively selected to survive, but those that respond to self ag are negatively selected to undergo apoptosis or cell death.

• T cell abnl can result in autoimmunity

T cell evaluation

• Begin with a CBC with diff. Determine the % of lymphs and the absolute lymph count.
  • In adults Lymphopenia <1000-1500 lymphs/mm3.
• Function can be assessed with:
  • DTH: Mumps, Trichophytan, Candida
  • Stimulation by Mitogens or Antigens then measure proliferation.
• CXR for child to see if thymus present.

T cells

• DDX
  • Primary immundeficiency:
    • SCID, Cartilage Hair (variant of short limbed dwarfism with fine hair and B&T cell abnl), DiGeorge,
  • Secondary Immunodeficiency:
    • Viral infections AIDS, malnutrition, autoimmune, malignancy, or loss ie intestinal lymphangiectasia.

B cells

• Cell line that produces Immunoglobulins: IgG, IgA, IgM, IgE

Abnl can result in complete absence of Ig, or the production of only some of the Ig. The production is determined by where the defect is in the differentiation of immunoglobulins.

• ie. X-linked agammaglobulinemia, Ig A deficiency, CVID

B Cells

• Maturation occurs in the bone marrow and is independent of ag.
  • involves an orderly sequence of gene rearrangement and cell proliferation.

terminal differentiation into plasma cells is dependent on cytokines. The various cytokine profiles determines which immunoglobulin is produced.

Biologic Properties of Ig

• IgG
  • chief component of the body's serologic defense - activates complement, promotes opsonization, crosses placenta
  • IgG response after initial ag challenge is associated with immunologic memory or anamnenstic response.
  • 4 subclasses : IgG1-protein, IgG2-polysacc, IgG3, IgG4-?blocking ab

Biologic Properties of Ig

• IgM

earliest antibodies identified in phylogeny and are the first class formed after ag stimulation. Appear within 4 days, but don't persist.

• Excellent at agglutinating ab and complement fixing. One of the first lines of attack.
• Isohemagglutinins - Blood Group antigens

Biologic Properties of Ig

• IgA
  • Secretory form is the chief defense against virus and bacteria at mucosal surfaces - sinopulmonary, GI.
  • Deficiency can be asymptomatic or can have problems with sinusitis, otitis, diarrhea, bronchitis, food allergy etc.
  • Can be associated with other immune def; IgG subclass deficiencies, CVID and SLE.

Biologic Properties of Ig

• IgE
  • felt to be beneficial in fighting parasitic infections.
  • elevated in some immunodeficiencies ie. Hyper IgE, Wiskott-Aldrich, DiGeorge, Hodgkin's disease.

B cells

• Screening Tests:

Quantitative Immunoglobulins, IgG subclasses, Isohemaglutinins, Ab response to vaccines ie: Tetanus, Diphtheria, HIB, Pneumococcus

Phagocytes

• Chemotaxis and Adhesion
  • abnl: LAD CD11a-c/CD18 , Hyper IgE
• Phagocytosis
• Intracellular Killing
  • Oxidative - NADPH enzyme system, utilizing electron cascade. abnl - CGD
  • Non oxidative utilize microbes own waste to produce superradicals ie. catalase

Phagocytes

• Screening Tests
  • WBC with diff, Nitroblue Tetrazolium Test, IgE level
  • Neutropenia needs to be ruled out.

Brief Overview of Compartment Cooperation

Macrophage will engulf then process bacteria for presentation to T cells. Once presented to T cells, various cytokines are released which can cause the differentiation of B cells into plasma cells and recruitment of other cells into the area of infection.

Complement

• Crucial role in
  • Bacterial lysis via osmotic lysis
  • Opsonization - phagocytes express receptors for opsonins which are complement proteins that bind to foreign surfaces
  • Activation of Inflammation - ie anaphylatoxins
  • Immune complex Solubilization.

Complement

• Classical and Alternative Pathways
  • Classical: complement activation by immunogloulin C1-C2-C4-C3
    • C1qesterase inhibitors shuts down the system
  • Alternative: direct activation of complement by binding to surface of infectious organism C3-
  • Membrane Attack Complex C3-C5-9
  • (protein cascade in the blood that acts like a tenderizer for the WBC)

Complement

• Abnl in early components C1-C4
  • Defects mimic B cell disorders - pyogenic infxn.
  • Defects can present as collagen-vascular disorders - SLE
• Abnl in terminal component results in recurrent Neisserial infections - menigitidis or gonorrhoeae.
• Most abnl are AR. Most common deficiency is C2 with increased autoimmunity, and pneumococcal infxn.

Cytokines - Overview

• IFN - antiviral, increases MHC I expression
• Interleukin -I - costimulator, acute phase reactant
• IL-2 - T cell growth factor produced by Tcells
• IL-4 - B cell growth factor and isotype switching to IgE
• GM-CSF - promotes growth and differentiation of these cells

History Intake

• HPI: Types, Age of Onset and Frequency of Infection
• PMH: Umbilical separation, vaccination history, environmental hx, travel hx, transfusions
• Family HX: Genetic tree, consanguinity, early childhood deaths
• PE: Growth, rashes, scars, adenopathy, presence of tonsils, nail abnormalities

General Treatment Plans

• Chronic disease with life time surveillance for infections, autoimmunity and malignancy.
• Some diseases will require replacement therapy such as IVIG others BMT.

Live Vaccines are contraindicated: MMR, OPV, Varicella. Some of these pts don't require any vaccines because they can't mount a response. (New Childhood Imm Schedule with IPV)

General Treatment Plans

• Many would recommend only CMV(-) irradiated blood in those less than 6months old and most patient who are immunosuppressed.

Primary Immunodeficiencies

• Bruton's Agammaglobulinemia
  • unable to produce immunoglobulins; X-linked
• Hyper IgE (Job's Syndrome)
  • recurrent abscess formation, coarse facies, eczema, abnl phagocytic chemotaxis.
• Common Variable Immunodeficiency
  • depressed immunoglobulins can have T cell abnl as well
• Chronic Granulomatous Disease
  • defect in oxidative burst leads to infection with catalase positive organisms. AR, X-linked

Primary Immunodeficiencies

• Complement Deficiencies
  • recurrent bacteremia, meningitis, SLE
• Ataxia-Telangiectasia
  • cerebellar ataxia, telangiectasia, IgA and IgG2 deficiency, CMI depressed, lymphosarcoma
• Wiskott-Aldrich Syndrome
  • X-linked infection, eczema and thrombocytopenia, ineffective T cells, High IgA
• DiGeorge Syndrome
  • absence of thymus, Congenital Heart Disease, hyopcalcemia, Chrm22 del

CASE STUDY 1

34 yo woman with 4 episodes of sinusitis and 2 episodes of pneumonia over last 14 mos. Also diagnosed with diarrhea due to giardia.

• PMH: anemia dx at 28yo.
• FH: mother and maternal aunt with SLE, father with autoimmune thyroiditis.
• PE: normal lymphoid tissue, tender max sinus otherwise normal exam.

Case Study 1

• DDX: antibody deficiency and complement def.
• Blood test:
  • IgG=145mg/dl >700
  • IgM=25mg/dl >50
  • IgA=12mg/dl >60
  • Normal # B&Tcells
  • CH50 normal
  • Poor functional ab.

CASE STUDY 1

• DX=CVID
  • 10% have pernicious anemia resulting in B12 deficiency.
• RX: Avoid live vacc.
  • Autoimmune w/u
  • Baseline PFT
  • IVIG

CVID

• Most clinically significant primary immunodef. that can present in adult life.
• Heterogeneous group of disorders of unknown etiology characterized by low serum Ig and impaired ab responses.
• Most common presentation is infection.
  • Sinopulmonary with encapsulated bacteria.
  • Chronic diarrhea
  • can have opportunistic infections ie. Pneumocystis, Herpes Zoster, fungi

CVID

• Often develop a variety of autoimmune disorders.
  • ITP, Autoimmune hemolytic anemia, Rheumatoid arthritis, Sicca syndrome, SLE, autoimmune thyroiditis, vitiligo.
• At risk for inflammatory disorders
  • IBD, celiac, nodular lymphoid hyperplasia.
• Inheritance unclear: some family members have IgA

CVID

• Usually have normal B cell count, but B cells can't differentiate into plasma cells
• Most have intact CMI, but some may have T cell abnormalities as well.

CASE STUDY 2

• 7 mos old African-American male with 2 hospitalizations
  • 1. 6 mos - Bronchiolitis ANC=47
  • 2. 7 mos - Pustules grew S.aureus
    ANC=63 on Discharge ANC=1873
• PMH: FT, umbilical separation at Day28, no previous infxn, good growth
• PE: no tonsillar tissue, healing pustules

CASE STUDY 2

• DDX: Phagocyte disorder vs antibody deficiency vs Hyper IgE
• Blood: IgG=27mg/dl IgA<7mg/dl IgM=70mg/dl CD20 and CD19 0.3% >5%
• ANC varies 40-1875

CASE STUDY 2

• DX: XLA with cyclic neutropenia
• RX: IVIG, no vaccinations, prophylactic antibiotics, genetic counseling

XLA or Bruton's

• Usually clinically evident in males after 6 months of age when transplacental maternal IgG is waning.
  • Paucity of lymphoid tissue
  • All isotypes are severely depressed
  • Flow Cytometry reveals absence of CD19 and CD20

XLA

• Defect is a mutation in Btk or B cell specific tyrosine kinase in formation of light chains.
• Maps to X chromosome Xq22
• 30% can have associated cyclic neutropenia.

Association with chronic progressive panencephalitis from enteroviruses, joint disease, dermatomyositis, autoimmune hemolytic anemia.

Workup

• Review history
• Physical Exam
• Screening Lab tests based on history

CBC with diff, Quantitative Immunoglobulins, IgG subclasses, IgE, Functional ab with isohemagluttinins, flow cytometry, NBT, mitogens, antigens