Disorders of the Immune System 2

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Disorders of the Immune System 2

• Richard A. McPherson, M.D.

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Cells of the Immune System

• Granulocytes/Neutrophils/Polymorphnuclear
  Granulocytes (PMNs, Polys)
• Lymphocytes
• Monocytes
• Eosinophils
• Basophils

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Neutrophil in Peripheral Blood
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Band (early neutrophil)
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Lymphocytes
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Atypical Lymphocytes (Viral Infection?)
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Cellular Immune System (Lymphocytes)

• T-lymphocytes CD2, CD3 markers
• 60-70 of peripheral lymphocytes also in lymph
  nodes spleen
• T cell antigen receptor binds to CD3 complex
• Somatic gene rearrangements (TCR)
• T cell proliferations
• (Mono)Clonal neoplastic
• Polyclonal non-neoplastic

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Malignant Lymphocytes (Clonal)
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T Cell Antigen Receptor Gene Rearrangement
(Clonal)
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T Lymphocytes

• CD4 helper T cells secrete cytokines
• 60 of CD3 T cells
• TH1 induce cellular immunity
• TH2 induce humoral immunity
• CD4 binds MHC class II for Ag presentation
• CD8 suppressor T cells cytotoxicity
• 30 of CD3 T cells
• CD8 binds MHC class I for Ag presentation
• CD4/CD8 ratio 21

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Flow Cytometry CD4, CD8 Normal
CD8
CD4
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Flow Cytometry CD4, CD8 Abnormal
CD8
Loss of CD4
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B Lymphocytes

• 10-20 of peripheral lymphocytes
• In bone marrow, lymph nodes, spleen, tonsils
• Antigen stimulation form plasma cells
• Secrete immunoglobulins IgM, IgG, IgA, IgD, IgE
• Ig antigen receptors on cell membranes of B cells
• CD19, CD20, CD21 B cell markers
• EBV infects B cells (infectious mononucleosus)
• Medication Rituximab Anti-CD20 against B-cell
  malignancies

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Plasma Cell (rarely seen in blood)
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Monoclonal Plasma Cell Disorders

• Multiple myeloma (IgG, IgA)
• Waldenstroms macroglobulinemia (IgM)
• Monoclonal gammopathy of unknown significance
  (MGUS)
• Occasionally B-cell lymphoma
• Finding a monoclonal spike in serum or urine
  usually leads to bone marrow examination, etc.

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Serum Protein Electrophoresis with Monoclonal
Spike of Immunoglobulin
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Confirmation by Immunofixation
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Clonality by Electrophoretic Mobility

• Polyclonal reactive, normal immune system
  response to stimulation (inflammation, infection)
• Monoclonal autonomous, neoplastic clone of
  plasma cells

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Scans of SPEP Immunoglobulin Variations
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Antigen Presentation

• Macrophages
• Process and present antigens to T cells
• Cytokine production
• Immunosurveillance/delayed hypersensitivity
• Dendritic/Langerhans cells
• Efficient Ag presentation MHC class II on
  surface
• Dendritic in lymphoid tissues
• Langerhans in epidermis
• Not phagocytic
• Fc receptors for trapping Ags/immunologic memory

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Granulocyte-Lymphocyte-Monocyte
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Natural Killer (NK) Cells

• 10-15 of peripheral lymphocytes
• No T-cell antigen receptors, no surface Ig
• Large granular (azurophilic) lymphocytes
• Lyse tumor, virus-infected cells without previous
  sensitization 1st line of defense
• CD2, CD3-, CD16, CD56
• CD16 Fc receptor to target IgG-coated cells
• Antibody-dependent cell-mediated cytotoxicity,
  ADCC

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Medication Herceptin (trastuzumab)

• Anti-breast cancer antibody
• Administered IV
• Ab coats tumor cells that have Her-2 (epidermal
  growth factor receptor 2 protein) on membrane
  surface
• Fc region of Ab sticks out
• NK cells recognize the Fc regions and destroy
  Ab-coated tumor cells by ADCC

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Large Granular Lymphocyte
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Cytokines

• Mediate natural immunity/inflammation IL-1,
  TNF-a
• Lymphocyte growth, activation, differentiation
  IL-2, IL-4, IL-5, IL-12, IL-15, TGF-b
• Activate inflammatory cells (non-specific)
  IFN-g, TNF-a, TNF-b, MIF
• Chemotaxis IL-8, eotaxin
• Hematopoiesis GM-CSF, G-CSF, stem cell factor,
  IL-3, IL-7

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New Medications for Immunomodulation

• Anti-CD20 for B-cell malignancy
• Rituxan (rituximab)
• Anti-TNF-a for rheumatoid arthritis, inflammatory
  bowel disease
• Remicade (infliximab)
• Enbrel (etanercept)
• Interferons
• Gamma stim immun
• Alpha HCV
• Granulocyte CSF Neupogen (filgrastim)

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Histocompatibility Genes (Ags)

• Bind peptide fragments of foreign proteins for
  presentation to T cells
• Chromosome 6
• Class I Ags HLA A, B, C on nucleated cells
• Class II Ags HLA D subregions DP, DQ, DR on
  macrophages, B cells, activated T-cells, vascular
  endothelial cells, fibroblasts, renal epithelium
  very complex identity
• Class III genes that map between I and II
  (Complement C2, C3, Bf, TNF a,b)

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Map of MCH Region on Chr 6
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Fine Map of MHC Class II
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HLA Complex

• Human leukocyte antigens
• Organ transplantation demonstrated barriers by
  cellular and humoral immunity
• Many alleles antigenic diversity and identity
• Class I present to CD8 cytotoxic T cells
• Class II present to CD4 helper T cells
• Modulation of immune response
• Disease assoc HLA-B27/ankylosing spondylitis
  DR4/rheumatoid arthritis DR3/Sjogrens syn,
  diabetes

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Structure of HLA Class I Ag Heavy chain plus
b2-microglobulin
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Structure of HLA Class II Ag 2 different heavy
chains
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Type I Hypersensitivity (Anaphylactic)

• Antigen binds to IgE on mast cells/basophils
• Initial (5-30 min) vasodilatation, vascular
  leak, smooth muscle spasm, bronchospasm, mucus
  secretion
• Late (2-8 hrs) inflammatory infiltrate/tissue
  destruction
• Primary mediators vasoactive amines (histamine),
  chemotaxis C3a, heparin, neutral proteases
• Secondary leukotrienes-vasoactive, spasmogenic,
  prostaglandin D2-bronchospasm, mucus PAF
  cytokines

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Medications

• Antihistamines
• Leukotriene receptor antagonists (LTRA)
• Montelukast
• Zafirlukast
• Epinephrine
• Steroids
• Methylated xanthines (theophylline)

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Basophil releases histamine
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Release of Histamine
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Type I HypersensitivityClinical Examples

• Local reaction on skin/mucosa urticaria, food
  allergies, hay fever, asthma
• Genetically controlled atopy familial
  disposition
• Benefit protects against parasitic infections

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Immunotherapy Ragweed Pollen
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Type II Hypersensitivity (Antibody Dependent)

• Target Ags on cell membranes
• Complement-mediated reactions
• Transfusion reactions to incompatible blood group
  Ag
• Rh incompatibility Rh neg mother, Rh pos fetus
  hemolytic disease of newborn Rhogam to all Rh-
  mothers with Rh babies
• Autoantibodies against RBCs, WBCs, platelets
• Antibody-Dependent Cell-Mediated Cytotoxicity
  (ADCC)
• Antibody-mediated cellular dysfunction
  autoantibodies against receptors

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Type III Hypersensitivity (Immune Complex
Mediated)

• Activation of complement accumulation of
  granulocytes that cause damage
• Systemic deposition of Circulating Immune
  Complexes in tissues
• Bacteria, viruses, self-Ag (DNA), serum sickness
• Kidneys, joints, skin, heart, serosa, small
  vessels
• Vasodilatation, edema, destructive enzymes,
  tissue necrosis
• Local (Arthus reaction)
• Acute immune complex vasculitis with tissue
  necrosis
• Farmers lung to mold on hay

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Necrotizing Vasculitis
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Type IV Hypersensitivity (Cell Mediated)

• Delayed hypersensitivity by CD4 T cells
• Example positive tuberculin skin test
  (intradermal)
• Local erythema/induration in 8-12 hr, peak 2-7 d
• Lymphocytes and monocytes migrate from vessels
• Transformation to granuloma
• Major defense against mycobacteria, fungi,
  parasites tumor immunity, transplant rejection
• Cellular cytotoxicity by CD8 cells

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Organ Transplant Rejection (cellular)

• T-cell mediated 10-14 days
• Foreign HLA Ags on graft
• CD8 cytotoxic T lymphocytes
• CD4 T cells secrete lymphokines
• Vascular permeability, mononuclear infiltrate,
  tissue ischemia
• Medications T-cell suppressants
• Cyclosporine
• Tacrolimus
• Sirolimus
• Rapamycin
• Mycophenolic acid

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Organ Transplant Rejection (Humoral)

• Antibody mediated
• Hyperacute (mins to hrs) preformed Abs
• Anti-HLA Abs form with T cell response
• Acute and chronic rejection
• Treatment plasma exchange to remove Abs

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Transplantation

• HLA match between donor and recipient
• Immunosuppression cyclosporine, FK-506, ALG
• Solid organs kidney, heart, lung, pancreas,
  liver
• Bone marrow transplant CD34 stem cells
• Autologous/allogeneic
• Graft vs host disease (GVHD) liver, skin,
  intestine (undesired)
• Graft vs tumor (leukemia) effect (desired)