Disorders of the Immune Response, Including HIV/AIDS

Disorders of the Immune Response, Including HIV/AIDS

• The human body is constantly at war with microscopic enemies. Thankfully, we have an internal defense mechanism designed to combat these threats.

• The purpose of the immune system is to recognize, disable, and dispose of all intruders – and then to remember them, in case they return at a later day.

Classification of Immunodeficiency States

• Primary (congenital or inherited)

• Secondary (acquired later in life)

  • Malnutrition

  • Infection (e.g., acquired immunodeficiency syndrome [AIDS])

  • Neoplastic disease (e.g., lymphoma)

  • Immunosuppressive therapy (e.g., corticosteroids or transplant rejection medications)

Results of Alterations of the Immune System

• Immunodeficiency states

• Allergic or hypersensitivity reactions

• Transplantation rejection

• Autoimmune disorders

Four Major Categories of Immune Mechanisms

• Humoral or antibody-mediated immunity (B lymphocytes)

• Cell-mediated immunity (T lymphocytes)

• The complement system

• Phagocytosis (neutrophils and macrophages)

Humoral Immunodeficiencies

• B-cell function and immunoglobulin or antibody production are involved.

• Defects in humoral immunity increase the risk of recurrent pyrogenic infections.

• Humoral immunity usually is not as important in defending against intracellular bacteria (mycobacteria), fungi, and protozoa.

• Viruses are usually handled normally, except for the enteroviruses that cause gastrointestinal infections.

Primary Humoral Immunodeficiency Disorders

• Genetic disorders of the B lymphocytes

• Approximately 70% of primary immunodeficiencies

• Immunoglobulin production depends on the following:

  • The differentiation of stem cells to mature B lymphocytes

  • The generation of immunoglobulin-producing plasma cells

• Can interrupt the production of one or all of the immunoglobulins

Immunoglobulins

• Immunoglobulin G (IgG)

  • 75% of all antibodies in the human body

• Immunoglobulin A (IgA)

  • Primarily found in mucosal tissues, such as those in the mouth, vagina, and intestines, as well as in saliva, tears, and breast milk.

  • 15% of all antibodies in the human body

• Immunoglobulin M (IgM)

  • One of the first antibodies recruited by the immune system to fight infection

  • Helps B cells "remember" a pathogen after it has been destroyed

• Immunoglobulin E (IgE)

  • Responsible for the allergic response that is mostly found in the lungs, skin, and mucosal membranes

• Immunoglobulin D (IgD)

  • Important in the early stages of the immune response

  • Does not actively circulate but instead binds to B cells to instigate the immune response.

Primary Humoral Immunodeficiency Disorders (Examples)

• Transient Hypogammaglobinemia

• Selective IgA

• Bruton’s Disease

• Transient hypogammaglobinemia

  • X-linked inherited condition

  • Hypogammaglobinemia

  • Failure of pre B-cells

• Bruton’s disease

  • Occurs in a baby who has inherited a gene that is linked to the x chromosome that prevents the B cells from maturing, produce no Abs, no IgG

  • Can develop a lot of bacterial infections

    • Bacterial meningitis

    • Respiratory infections

• Selective IgA

  • The only Ab they cannot produce IgA

  • IgA found in tears, saliva, etc., therefore these are the areas likely to get infections

T-cell Immunodeficiencies

• DiGeorge disease

  • Lack of development of the thymus – T-cells can’t mature

  • Viral infections, CA

  • These babies have a lot more than just T-cell deficiencies

  • T-cells develop about the same time as many of the features of the head

  • A lot of deformed facial features

• SCIDS

  • Severe combined immune deficiency syndrome

  • Problem of stem cell development

  • Can’t produce either B or T cells

  • In these babies, they have no immune system

  • Symptoms vary much like AIDS

  • If not treated they die of some infection within a year of two

  • Can be treated with stem cell – bone marrow transplant

  • Boy in the bubble

Combined T-Cell and B-Cell Immunodeficiencies

• Severe combined immunodeficiency

• X-linked SCIDS

• Ataxia-telangiectasia

• Wiskott-Aldrich syndrome

Disorders of the Complement System

• Primary

  • Most inherited as autosomal recessive traits and can involve one or more complement components

• Secondary

  • Can occur in persons with functionally normal complement systems because of rapid activation and turnover or reduced synthesis of complement components

• Hereditary angioneurotic edema and loss of regulation

The Phagocytic System

• Action of these cells:

  • Migrate to the site of infection

  • Aggregate around the affected tissue

  • Envelope the invading microorganisms

  • Generate microbicidal substances to kill the ingested pathogens

• Definition: composed primarily of polymorphonuclear leukocytes and mononuclear phagocytes

Dysfunction of the Phagocytic System

• A defect in phagocytic functions or a reduction in the absolute number of available cells disrupts the system.

• Susceptible to

  • Candida species

  • Filamentous fungi

  • Chronic granulomatous disease (CGD)

Adaptive Immunity

• Development of response to the antigen

• Specific humoral and cellular recognition

• Memory cells

Immunoglobulins (Review)

• IgA – found in saliva and tears, vaginal secretions, bronchial, GI, prostatic; primarily found in secretions

• IgD – primary function unknown

• IgG – the most abundant; present in all body fluids; the only Ab that crosses the human placenta

• IgE – involved in inflammation and allergic responses; involved in combating parasites

• IgM – the first antibody to be produced by the developing fetus

Hypersensitivity Disorders

• Definition

  • Excessive or inappropriate activation of the immune system

• Types

  • Type I, IgE-mediated disorders

  • Type II, antibody-mediated disorders

  • Type III, complement-mediated immune disorders

  • Type IV, T-cell–mediated disorders

Types of IgE-Mediated Allergic Reactions

• Atopic Disorders

  • Heredity predisposition and production of a local reaction to IgE antibodies produced in response to common environmental agents

  • Urticaria (hives), allergic rhinitis (hay fever), atopic dermatitis, food allergies, some forms of asthma

• Nonatopic Disorders

  • Lack the genetic component and organ specificity of the atopic disorders

Phases of Type I Hypersensitivity Reactions

• Primary or Initial-phase Response

  • Vasodilation

  • Vascular leakage

  • Smooth muscle contraction

• Secondary or Late-phase Response

  • More intense infiltration of tissues with eosinophils and other acute and chronic inflammatory cells

  • Tissue destruction in the form of epithelial cell damage

Type II (Cytotoxic) Hypersensitivity Reactions

• Action

  • Mediated by IgG or IgM antibodies directed against target antigens on the surface of cells or other tissue components

  • Endogenous antigens: present on the membranes of body cells

  • Exogenous antigens: absorbed on the membrane surface

• Examples

  • Mismatched blood transfusion reactions

  • Hemolytic disease of the newborn

  • Certain drug reactions

Type III, Immune Complex Allergic Disorders

• Mediated by the formation of insoluble antigen–antibody complexes that activate the complement pathway

• Activation of the complement pathway by the immune complex generates chemotactic and vasoactive mediators that cause tissue damage by

  • alterations in blood flow

  • increased vascular permeability

  • destructive action of inflammatory cells

• Immune complexes formed in the circulation produce damage when in contact with the vessel lining or are deposited in tissues.

• They elicit an inflammatory response by activating the complement pathway.

• Leading to chemotactic recruitment of neutrophils and other inflammatory cells.

• Responsible for the vasculitis seen in certain autoimmune diseases

• Systemic immune complex disorders

  • Serum sickness

• Localized immune complex reactions

  • Arthus reaction

Type IV Hypersensitivity Reactions

• Cell-Mediated Immune Response

  • The principal mechanism of response to a variety of microorganisms, including intracellular pathogens and extracellular agents

  • Can lead to cell death and tissue injury in response to chemical antigens or self-antigens

• Basic Types

  • Direct cell-mediated cytotoxicity

    • Hepatitis

  • Delayed-type hypersensitivity

    • Allergic contact dermatitis

  • Hypersensitivity pneumonitis

Routes of Exposure to Latex

• Cutaneous

• Mucous membrane

  • Most severe reactions resulted from contact with the mouth, vagina, urethra, or rectum

• Inhalation

• Internal tissue

• Intravascular routes

• Reaction types

  • Type I versus type IV

Histocompatibility Complex

• Major histocompatibility complex

  • Set of molecules displayed on cell surfaces

  • Lymphocyte recognition

  • Antigen presentation

  • Controls the immune response through recognition of "self" and "nonself"

Categories of Transplanted Tissue

• Allogeneic (allograft)

  • The donor and recipient are related or unrelated but share similar HLA types.

• Syngeneic

  • The donor and recipient are identical twins.

• Autologous

  • The donor and recipient are the same person.

Allogeneic, Syngeneic, Autologous (Detailed)

• Allogenic (allograft)

  • Host and donor share similar DNA; share similar HLA type

• Syngeneic (isograft)

  • Host and donor are identical twins; identical HLA type

• Autologous

  • Host and donor are the sane

  • Host and donor share similar DNA

  • Self-to self

  • Skin graft

  • Blood transfusion

  • Bone marrow transplant

HVGD GVHD

• HVGD

  • Host vs graft disease – referred to as transplant rejection

  • The disease that occurs – hypersensitivity disease Type IV

  • T cell mediated vs foreign HLA

  • The t cells of the person recognizing the transplanted cells of the organ

  • Th stimulated to produce cytotoxic T cells (these will destroy whatever the transplant is

• GVHD

  • Graft vs host disease

  • The transplant rejects the person

  • The only situation this can happen:

  • Those that are particularly attacked are epithelial cells

  • A bone marrow transplant

Stem Cell Transplantation

• Many primary immunodeficiency disorders traced to deficiency in stem cells can be cured with allogeneic stem cell transplantation from an unaffected donor.

• SCIDs, Wiskott-Aldrich syndrome, and chronic granulomatous disease

• Stem cells can repopulate the bone marrow and reestablish hematopoiesis.

• To be effective, the bone marrow cells of the host are destroyed by myeloablative doses of chemotherapy.

Mechanisms Postulated to Explain the Tolerant State

• Self-tolerance

  • Central tolerance

    • The elimination of self-reactive T cells and B cells in the central lymphoid organs (i.e., the thymus for T cells and the bone marrow for B cells)

  • Peripheral tolerance

    • Derives from the deletion or inactivation of autoreactive T cells or B cells that escaped elimination in the central lymphoid organs

Basic Patterns of Transplant Rejection

• Hyperacute Reaction

  • Occurs almost immediately after transplantation.

  • Produced by existing recipient antibodies to graft antigens initiating a type III, Arthus-type hypersensitivity reaction

• Acute Rejection

  • Occurs within first few months after transplantation with signs of organ failure; may occur months or years after immunosuppression has been terminated

  • T lymphocytes respond to antigens in the graft tissue

• Chronic Host-versus-Graft Rejection

  • Occurs over a prolonged period.

  • Manifests with dense intimal fibrosis of blood vessels of the transplanted organ.

  • The actual mechanism is unclear but may include release of cytokines that stimulate fibrosis.

Basic Requirements Necessary for GVHD

• The transplant must have a functional cellular immune component.

• The recipient tissue must bear antigens foreign to the donor tissue.

• The recipient immunity must be compromised to the point that it cannot destroy the transplanted cells.

Autoimmune Diseases (Examples)

• Systemic lupus erythematosus (SLE)

• Autoimmune hemolytic anemia (AIHA)

• Pemphigus vulgaris

• Hashimoto thyroiditis

Mechanisms of Autoimmune Disease

• Heredity and gender

• Failure of self-tolerance

• Disorders in MHC–antigen complex/receptor interactions

• Molecular mimicry

• Superantigens

Criteria for Determining an Autoimmune Disorder

• Evidence of an autoimmune reaction

• Determination that the immunologic findings are not secondary to another condition

• The lack of other identified causes for the disorder

The AIDS Epidemic and Transmission of HIV Infection

• Transmission of HIV Infection

  • Sexual contact

  • Blood-to-blood contact

  • Perinatally

    • Transmission from mother to infant is the most common way that children become infected with HIV.

Pathophysiology and Clinical Course of HIV/AIDS

• Molecular and Biologic Features of HIV

• Classification and Phases of HIV Infection

  • Phases of HIV Infection

    • Primary infection phase

    • Chronic asymptomatic or latency phase

    • Overt AIDS phase

Clinical Course of HIV/AIDS

• Opportunistic Infections

  • Respiratory Manifestations

    • Pneumonia

      • Pneumocystis jirovec

      • Mycobacterium avium intracellulare

      • Cytomegalovirus

      • COPD

  • Gastrointestinal Manifestations

    • Diarrhea

      • Protozoa

        • Cryptosporidium

        • Isospora bell

        • Giardia lamblia

      • Bacteria:

        • Mycobacterium avium intracellulare

      • Viruses:

        • Cytomegalovirus

  • CNS

    • Cryptococcal meningitis

    • Toxoplasmosis

    • Papovavirus (Progressive multi-focal leukoencephalopathy)

  • MUCOCUTANEOUS

    • Herpes simplex

    • Candidiasis

  • SKIN

    • Staphylococcus

    • Scabies

    • HPV

    • Molluscum contagiosum

    • Kaposi sarcoma

• Nervous System Manifestations

• Cancers and Malignancies

• AIDS dementia

• LYMPHOPROLIFERATIVE DISEASE

  • CNS lymphoma

  • Persistent generalized

  • lymphadenopathy

  • B-cell lymphoma

• AIDS nephropathy

Prevention, Diagnosis, and Treatment of HIV/AIDS

• Prevention

• Diagnostic Methods

  • Enzyme immunoassay (enzyme-linked immunosorbent assay)

  • Western blot antibody detection tests for HIV infection

• Treatment

  • Reverse transcriptase inhibitors

  • Protease inhibitors

  • Fusion inhibitors

HIV Infection in Pregnancy and in Infants and Children

• Preventing perinatal HIV transmission

• Diagnosis of HIV infection in children