Disorders of the Immune System

1
The Nature of DiseasePathology for the Health
Professions Thomas H. McConnell

• Chapter 3
• Disorders of the Immune System

2
Brief Review of Adaptive Immunity
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
3
Overview of Immune Disorders

• Immune disorders fall into 3 major categories
• Hypersensitivity disorders
• Caused by an allergen (antigen causing an
  allergic resp.)
• Allergic rhinitis, anaphylaxis
• Autoimmune disorders
• Immune system attacks self
• RA, SLE
• Immunodeficiency disorders
• Absent or depressed immune response (primary
  acquired)
• DiGeorge syndrome, AIDS

4
Hypersensitivity

• Exaggerated immune response
• Environmental or internal antigens
• Associated more closely with certain HLA
  genotypes
• Four types
• Type I immediate hypersensitivity (allergic
  anaphylactic) B cell
• Type II cytotoxic hypersensitivity B cell
• Type III immune-complex hypersensitivity B
  cell
• Type IV cellular hypersensitivity (delayed) T
  cell
• Mnemonics ACID and AnGST

5
Type I (Immediate) Hypersensitivity
Important points - Immediate (after initial
sensitization) - Antigen is extrinsic (foreign)
- Local or systemic - B cell (ab) mediated -
IgE - Mast cells (histamine other mediators) -
Examples - Allergic rhinitis (seasonal hay
fever) - Anaphylaxis (local or systemic)
- One form of latex allergy (to the latex itself)
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
6
Type II (Cytotoxic) Hypersensitivity
Important points - Usually immediate (gt
sensitization) - Ag is extrinsic or intrinsic -
May be initiated by a hapten - Local or
systemic - B cell (ab) mediated - IgG or IgM -
Ab attach to cell surface - Cell injury from
- Complement - NK Cell, phagocytes (ADCC)
- Altered cell function - Examples -
Txfusion Rexn - Graves Disease -
Myasthenia Gravis - Autoimmune hemolytic
anemia
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
7
Type III (Immune Complex) Hypersensitivity
Important points - Usually immediate (gt
sensitization) - Antigen not fixed in tissue -
Local or systemic hypersensitivity - B cell (ab)
mediated - IgG or IgM - Damage from ag-ab
complexes - Examples - SLE - Serum
sickness - Farmers Lung - One form of
latex allergy (to the latex itself)
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
8
Type IV (Delayed Type) Hypersensitivity
Important points - Delay (28-48 hrs) - T cell
mediated - Damage from TCTL attack - Examples
- TB - Transplant rejection - Contact
dermatitis (poison ivy) - Latex allergy (to
chemicals used) - Granulomatous inflammation
- Rheumatoid arthritis - Multiple
sclerosis - Type I Diabetes Mellitus
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
9
Allergic Disorders and Atopy

• Allergy Exaggerated, but otherwise normal immune
  response to foreign antigen (regardless of the
  type of hypersensitivity response)
• Allergen an inciting foreign substance
• Atopy allergy due to type I hypersensitivity
• Common
• Usually affect nose, skin, and airways (-gt
  atopic triad rhinitis, dermatitis, asthma
• Strong familial (genetic) tendency
• Pathophysiology is from IgE-sensitized mast cells
• Food allergies (infants milk, soy, eggs,
  peanuts, wheat adults usually nuts and seafood)
• Anaphylaxis

10
Autoimmune Disorders

• Self antigens become targets of the immune system
• Affects 2 of US population autoimmune ab
  common, especially in elderly
• Clinical manifestations are extremely varied
• Genetic susceptibility, e.g., HLA-B27 and
  rheumatoid disease
• Some hypothesized causes
• Imperfect T and B cell programming
• Inaccessible self-antigens that become exposed
  for the first time to the immune system
• Molecular mimicry
• antigenic determinants of an infectious agent or
  foreign protein may be shared with self antigens
• Ab produced by B cells cross-react with self
  antigens
• Infection and inflammation

11
Selected Autoimmune Disease
12
Systemic Lupus Erythematosus (SLE)

• Chronic inflammatory, rheumatic, autoimmune
  disease characterized by remissions and
  exacerbations
• Etiology unknown (UV?, genetic?, hormonal?)
• Leukemia and renal failure usually major cause of
  death
• Classifications
• Systemic lupus - involvement of 1 or more of
  these systems Musculoskeletal, Lungs, Kidneys,
  CNS, CVS, hematological
• Discoid lupus - limited to skin involvement
• Drug-induced lupus procainamide, hydralazine,
  isoniazid
• Pathophysiology
• Anti-DNA/RNA (antinuclear) autoantibodies
  produced by hyperactive B cells
• Detection test is very sensitive, but not very
  specific
• Other autoantibodies against RBCs, platelets,
  lymphocytes
• Autoantibodiesantigens -gt Type III immune
  complex disease
• IC cause vasculitis with inflammation and
  necrosis

13
Systemic Lupus Erythematosus (SLE)
Malar (butterfly ) phtotsensitive rash
Figures from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
14
Scleroderma (Systemic Sclerosis)

• Pathophysiology
• Etiology unknown (genetic?, immune?,
  environmental?)
• Microvascular damage, inflammation, fibrosis of
  interstitium
• Many organs can be affected, especially the
  dermis
• Types of scleroderma
• Systemic sclerosis
• CREST syndrome
• Calcinosis
• Raynauds phenomenon
• Esophageal dysfunction
• Sclerodactyly
• Telangiectasis
• Localized or limited skin on fingers, hands, and
  face (better prognosis)

15
Amyloidosis

• Amyloid mixture of insoluble, mis-folded,
  crystalline proteins some may be Ig fragments
• Amyloidosis Any dysfunction resulting from
  deposition of amyloid protein
• Examples
• Light chain amyloidosis (in B cell malignancies)
• Reactive systemic (with chronic inflammatory
  disease)
• Hereditary (primary) amyloidosis caused by
  several gene defects, e.g., hereditary
  Mediterranean fever
• Amyloidosis of aging
• Islets of Langerhans (Type II diabetes)
• Endocrine tumors (some)
• Brains of patients with Alzheimers Disease

Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
16
Tissue Transplantation

• Successful transplantation is highly dependent
  upon having as close a match as possible between
  tissue antigens (MHC/HLA and ABO) of donor and
  recipient
• Except for an autograft, every transplant has a
  possibility of rejection immunosuppressive
  therapy
• Types of rejection (an immune reaction)
• Hyperacute minutes or hours due to preformed ab
• Acute
• most common and treatable
• T and B cells involved
• Rejection mediated by cellular immune response
• Signs of inflammation with fever, redness,
  swelling, tenderness
• Chronic 4 months to years causes chronic
  vasculitis compromising blood flow to transplant

17
Graft versus Host Disease (GvHD)

• Frequent and potentially fatal complication of
  bone marrow transplant
• Immunocompetent cells of the donor recognize the
  recipients tissues as foreign
• Cell-mediated response
• Host is typically immunocompromised and unable to
  fight grafted cells attack
• Other areas affected skin and GI tract (lots of
  epithelial cells), liver
• Acute GvHD dermatitis, diarrhea, jaundice
• Chronic GvHD dermal sclerosis, Sjogrens
  syndrome, immunodeficiency

18
Transfusion Reactions

• Minimized by careful testing prior to
  transfusion
• Major crossmatch donor RBCs with recipient
  plasma
• Minor crossmatch donor plasma with recipient
  RBCs
• Two major types of transfusion reactions
• Major
• Incompatible blood types
• Recipients pre-existing ab hemolyzes of donors
  RBCs
• Severe hemolysis, thrombosis, DIC, renal failure,
  death
• Minor
• Any rexn NOT potentially life-threatening
• Fever, chills, back pain, hives, rash
• Erythroblastosis Fetalis (hemolytic disease of
  the newborn) - mother generates anti-Rh
  antibodies against fetal RBCs

19
Immune Deficiencies

• Failure of immune mechanisms of self-defense
• Primary (congenital) immunodeficiency
• Genetic anomaly
• Secondary (acquired) immunodeficiency
• Caused by another illness
• Clinical presentation
• Development of unusual or recurrent, severe
  infections (usually opportunistic infections)
• T cell deficiencies
• Viral, fungal, yeast, and atypical microorganisms
• B cell and phagocyte deficiencies
• Microorganisms requiring opsonization (bacteria,
  some viruses)
• Complement deficiencies

20
Primary Immunodeficiencies

• Affect the development of T and B cells
• Isolated IgA deficiency (B cells)
• Most common primary immunodeficiency
• Recurrent infections of mucous membranes
• X-linked agammaglobulinemia -Bruton Disease (B
  cells)
• X-linked recessive defect of B cell development
• Recurrent infections by about 6 months of age
• Bronchitis, pneumonia, sinusitis, pharyngitis,
  otitis, GI infections
• Intestinal parasites and certain viral infections
• Thymic hypoplasia (DiGeorge syndrome) (T cells)
• Deficient T cell function due to failure of
  thymus to develop
• Area around thymus often affected neck, face,
  ears, heart, aorta
• Viral, fungal, protozoan infections
• Severe combined immunodeficiency - SCID (B and T
  cells)
• Lymphoid tissues and thymus underdeveloped lack
  of functional immunity
• Wide variety of infections before 6 months of
  age total isolation required

21
Acquired Immunodeficiency Syndrome (AIDS)

• By far most common cause of acquired (secondary)
  immunodeficiency
• Follows infection with Human Immunodeficiency
  Virus (HIV-1 (US), HIV-2 (W. Africa))
• Humans are the only reservoir no animal
  reservoir
• Virus attaches to CD4 antigen of TH (and related
  macrophages) but must also use several other
  receptors (chemokine) to infect, i.e, CD4 is
  necessary but not sufficient for infection
• Reverse Transcriptase (RT) allows the RNA genome
  to be reverse transcribed into DNA, and the
  abnormal DNA is inserted into host genome
• Corrupted cellular DNA produces new HIV RNA and
  virus particles
• Virus particles exit dying cell to infect other
  cells

Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
22
Additional HIV/AIDS Terminology Facts

• Modes of transmission for HIV virus
• Contact with infected blood or blood products
  during transfusion or transplantation
• Contact with infected body fluids, e.g., semen,
  vaginal fluids
• Across the placenta from infected mother to fetus
  
• Although HIV is also found in saliva, urine,
  tears, and feces theres no evidence of
  transmission through these fluids
• Viral load - number of circulating HIV
  particles/ml (should be zero)
• Opportunistic infection Any infection resulting
  from a deficient immune system, i.e., patient is
  immunocompromised or immunosuppressed
• Peripheral blood CD4 TH cell counts are a
  reliable indicator about the progress of the
  disease the lower the counts the more advanced
  the disease and the poorer the prognosis
• Current treatment regimen (Highly Active
  Antiretroviral Therapy, HAART) has dramatically
  extended the life expectancy of HIV-infected
  patients

23
Phases of HIV Infection and AIDS
Figure from McConnell, The Nature of Disease,
2nd ed., Wolters Kluwer, 2014
24
Classification of HIV Infection/AIDS is complex
Immunocompetent
Immunosuppressed
AIDS
Table from http//aidsetc.org/guide/hiv-classific
ation-cdc-and-who-staging-systems

• Category B symptomatic conditions are defined
  as symptomatic conditions occurring in an
  HIV-infected adolescent or adult that meet
  atleast one of the following criteria
• They are attributed to HIV infection or indicate
  a defect in cell-mediated immunity.
• They are considered to have a clinical course or
  management that is complicated by HIV infection.
• Category C AIDS Indicator conditions include
• - Wasting syndrome caused by HIV (involuntary
  weight loss gt10 of baseline body weight)
  associated with either chronic diarrhea (two or
  more loose stools per day for 1 month) or
  chronic weakness and documented fever for 1
  month
• - A number of associated conditions, e.g.,
  Bacterial pneumonia, recurrent (two or more
  episodes in 12 months) Candidiasis of the
  bronchi, trachea, or lungs Candidiasis,
  esophageal Cervical carcinoma, invasive,
  confirmed by biopsy Coccidioidomycosis,
  disseminated or extrapulmonary Encephalopathy,
  HIV-related ,Kaposi sarcoma Mycobacterium
  tuberculosis, pulmonary or extrapulmonary
  Pneumocystis jiroveci (formerly carinii)
  pneumonia (PCP) Toxoplasmosis of brain