Immunopathology (trans 3 - half) Flashcards
IMMUNOPATHOLOGIC STATES
- IMMUNOPATHOLOGIC STATES
- HYPERACTIVE
- AUTOIMMUNITY
IMMUNODEFICIENCY:
o Possible causes: infection or tumor
o Presence of INFECTION: the organism will destroy the tissue that is supposed to be fighting off the foreign bodies
o Presence of TUMOR: malignant cells will destroy the normal cellular element
o Body cannot react properly to the stimulus of an antigen.
o An individual becomes easy prey for infections and tumor development.
HYPERACTIVE:
o OPPOSITE STATE of immunodeficiency
o Hypersensitivity diseases, which could lead to a fatal disease (e.g., an overwhelming allergic reaction).
AUTOIMMUNITY:
o Immune system loses its normal capacity to distinguish self from non-self
Under normal conditions, there is a degree of tolerance of antibodies (Ab) against your own tissue.
In contrast, when recognition problem arises, the tissue native to your own body becomes antigenic. This then prompts the immune system to destroy one’s own tissue.
TYPES OF IMMUNITY - INNATE IMMUNITY
Natural or native immunity
Type of immunity that you have BEFORE you are born
Present BEFORE infection
First line of defense
NEUTROPHILS are the first responders (24-48 hours of infection), which are responsible for recruitment of cells to site of infection
Non-specific (antigen-independent) mechanism
Rapid immune response, occurring within minutes or hours after aggression
No immunologic memory
Promotes clearance of dead cells or antibody complexes, and removal of foreign substances present in organs, tissues, blood and lymph.
Activates the adaptive immune response through a process known as ANTIGEN PRESENTATION
Peptide, the by-product of the microorganism, is the one presented not the entire cell.
BARRIERS of innate immunity
TYPES OF IMMUNITY - INNATE IMMUNITY
Anatomical
SKIN
- Intact lining epithelium/barrier that offending organisms cannot enter
- Has an acidic environment (pH 3-5) due to sweat that hinders growth of microbes
- E.g., During rainy season, cases of Leptospirosis is common due to exposure to flood water contaminated with urine of infected rats. When there is a flaw in the epithelial barrier, offending organisms can easily gain access into the vascular system.
MUCOSAL MEMBRANE/LINING EPITHELIUM
- Found in the nasal, oral, intestinal, vaginal, and urethral mucosa
- Normal flora compete with microbes for attachment sites
- Mucous entraps foreign microbes
- Cilia propel microbes out of the body
- This should be intact because in peptic ulcer cases, offending organisms can invade the blood vessel through the lamina propria of the lining epithelium
Physiological
TEMPERATURE
- It can inhibit the growth of some pathogens
- Body temperature – 37°C
- Fever – >37°C
PH
- Low pH (ACIDIC): Gastric acid secretions – it is detrimental to some bacteria
- High pH (BASIC): Intestinal secretions (BILE) – it can also help to protect the body from offending organisms
CHEMICAL MEDIATORS
- Lysozymes that cleave bacterial cell wall: Enzymes found in tears can dissolve offending organisms
- INTERFERON induces antiviral defenses in uninfected cells, such as the recruitment of NK cells. It does not protect the infected cell. It protects the uninfected surrounding cells
- PLASMA PROTEINS => COMPLEMENT (C1 to C9) lyses microbes or facilitates phagocytosis
TYPES OF IMMUNITY - ADAPTIVE IMMUNITY
Acquired/Specific Immunity
Type of immunity acquired AFTER exposure to pathogen
Immune response AFTER you are born
Consists of lymphocytes and antibodies
More powerful than innate immunity in combating infections
Antigen-dependent and antigen-specific
Has the capacity for memory, which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen
By convention, immune system and immune response = adaptive immunity
Can be active or passive
o Active Immunity- through vaccination or previous infection (ex. Chickenpox)
o Passive Immunity- transfer of antibody/lymphocytes from an immune donor (ex. Maternal Placental transfer of Abs)
o TYPES of Adaptive Immunity
Humoral immunity – mediated by soluble proteins called antibodies that are produced by B lymphocytes or B cells
Cell-mediated immunity – mediated by T lymphocytes or T cells.
o COMPONENTS of Adaptive Immunity
Lymphocytes and products of the adaptive immune system
Lymphocytes – responsible for acquired immunity, it happens when antibodies, produced by B cells, encounter an antigen
Dendritic cells, cytokines, and complement system enhance the effectiveness of antibodies and are also involved in activating the Classical Pathway of the complement system
CELLS AND TISSUES OF IMMUNE SYSTEM - Lymphocytes
T Lymphocytes or T CELLS
o Thymus-derived
o Majority of the lymphocytes: 60-70% - Found in paracortical areas and interfollicular zones of lymph nodes and periarteriolar sheaths of the spleen.
o Do not detect free or circulating antigens, instead, the vast majority of the T cells recognize only PEPTIDE FRAGMENTS bound to MHC.
o MHC Restriction – recognition of peptides displayed by self MHC molecules.
o Has T CELL RECEPTORS to recognize peptide antigens presented by self MHC molecules
T cell receptors (TCR) – polymorphic antigen binding molecules, analogous to surface immunoglobulin that binds antigen-associated MHC on other cells.
Utilized in organ transplantation
o Functions
Participates in cellular immune response as the effector cells, and “helper cells” for the antibody responses to protein antigens.
Interacts with other cells – either (i) to kill infected cells or (ii) to activate phagocytes or B lymphocytes that have ingested the protein antigens
SUBSETS of T Cells
Cytotoxic T Cell
- Has CD8 receptor on its surface
- Known as Tc, cytotoxic T lymphocyte (CTL), T killer cell/killer T cells, or CD8+ T cells (CD8- expressing T cells)
- It is toxic to the offending organism since it will be utilizing different hypersensitivity reactions
- Majority of the circulating blood lymphocytes – 70-80%
- Terminator of foreign substances; 30% express CD8+ surface receptors which destroy host cell harboring microbes
- Puncture Ag cell membrane => inject enzymes
- Bind on Ag surface receptors => reactions within the infected/abN cell => cell death
- Also active in tumor surveillance
Helper T Cell
- Has CD4 receptor on its surface
- CD4+ T cell or CD4-expressing T cell
- Helps activate cytotoxic T cells to kill infected or abnormal cells
- Secretes soluble molecules (cytokines) that help B cells to produce antibodies
- Helps macrophages to destroy phagocytosed microbes
- Types of helper T cells
- Th1 – stimulates production of most opsonizing and complement fixing antibodies; IgG antibodies respond to many bacteria and viruses; synthesizes and secretes IL-2 and IFN-G
- Th2 – secretes cytokines that stimulate the production of IgE and activate eosinophils in response to helminthic infection; produces IL-4, IL-5 and IL-3
Suppressor T Cell
- It expresses all pan T-markers (CD3, CD2 and CD5) but the predominant is the CD8 receptor on its surface
- Produce substances that help end the immune response or sometimes prevent certain harmful responses from occurring
- Decreases immune reaction detrimental to the organ
CELLS AND TISSUES OF IMMUNE SYSTEM - Lymphocytes
B LYMPHOCYTES or B CELLS
o Bone marrow-derived
o 10-20% of lymphocytes, lesser in number
o After stimulation, B cells differentiate into plasma cells that secretes large amounts of antibodies (the mediators of humoral immunity)
o Anatomic residence:
Blood
Cortex of lymph nodes and germinal centers
Tonsils and other mucosal tissue
Splenic white pulp and lymphoid follicles
Bone marrow
o Functions
Recognizes antigen by means of membrane-bound antibody of the IgM class, expressed on the surface together with signaling molecules to form B cell receptor
Can recognize and respond to many more chemical structures including soluble or cell-associated proteins, lipids, polysaccharides, nucleic acids and small chemicals
Recognizes almost limitless number of different antigens
Main function is to produce antibodies
Can also present antigen to T cells
o B cell responses to antigens (remember, antigens are PROTEINS) require help from CD4+ T cells => engages CD40, necessary for B cell maturation and secretion of IgG, IgA and IgE antibodies
o CD40: member of the TNF-receptor family
o Activated helper T lymphocytes express CD40 ligand, which specifically binds to CD40 expressed on B cells
o Mutation in CD40 ligands => immunodeficiency X-linked Hyper IgM syndrome
o X-linked Hyper IgM syndrome results to non- production of IgG. Mutation can either be translocation, amplification or point mutation
CELLS AND TISSUES OF IMMUNE SYSTEM - Lymphocytes
Natural Killer Cells
o Lymphocytes from the common lymphoid progenitor that gives rise to T cells and B cells: 10-15% of peripheral lymphocytes
o Do not have T cell receptors, surface Ig nor traditional T or B markers: They cannot display antigen for the macrophage to phagocytose.
o Morphologic name: Large Granular Lymphocytes
However, NK cells are cells of innate immunity
Do not express highly variable and clonally distributed receptors for antigens.
They do not have specificities as diverse as do T cells or B cells.
Have 2 receptors: inhibitory and activating
Inhibitory receptors recognize self MHC class I molecules that are expressed by healthy cells =\> prevents destruction of normal cells Activating receptors recognize molecules that are expressed or upregulated on stressed or infected cells or cells with DNA damage =\> prompts destruction of infected cells
o Act in both Innate and Adaptive immune response (one at a time)
o Kill variety of tumor cells, virally infected cells, some normal cells without previous sensitization
o Killing dependent on cell to cell contact enhanced by interferon and IL-2
o Antibody dependent cell-mediated cytotoxicity (ADCC): ability to lyse IgG coated target cells due to CD16 cell surface molecules
o Secrete cytokines such as IFN-gamma (macrophage activating)
o In contrast to Natural Killer T (NKT) cells, NK cells do not express:
T-cell Antigen Receptors (TCR)
Pan T marker
CD3
Surface immunoglobulins (Ig) – B cell receptors express this
o NK Cells usually express
Surface markers CD16 (FcγRIII)
CD56 in humans
Express CD8 in up to 80%
Pan Markers for T and B Cells
CD19 - pan B marker
B lymphoid lineage – surface Ig (SIg) or cellular Ig (CIg)
If you suspect a B cell lymphoma, you would test these markers
CD2, CD3, CD5, CD7 – pan T cell antibodies
Present on most normal mature T cells
T cells – CD2 and CD3
CELLS AND TISSUES OF IMMUNE SYSTEM - antigen presenting cells
Macrophages
Second line of defense
Arises when neutrophil (the first line of defense) cannot contain the
Functions
Phagocytosis of cellular debris and pathogens
Ingestion of microbes and other particulate antigens and display peptide recognition by T lymphocytes. Then T lymphocytes activate the macrophages to kill the microbes. - The central reaction of cell-mediated immunity
Stimulation of lymphocytes and other immune cells that respond to the pathogen
Lifetime
Activated: days
Immature: months to years
o Cytokine activation of CD4+ cells enhances microbicidal properties of macrophages and augments their ability to kill tumor cells
o Induction of cell mediated immune response: process the antigens in phagocytosed microbes and present peptide fragments to T cells
o Effector phase of humoral immunity: phagocytose microbes opsonized by IgG or C3b
o Fixed leukocytes/macrophages: migrated into the tissues of the body to take up a permanent residence at that location
Kupffer cell – liver
Histiocytes
Langerhans cells – epidermis
Alveolar macrophages – alveolar wall (involved in congestive heart failure, heart failure cells, when blood goes out of the vessel, the macrophages phagocytose them)
Serous and peritoneal cavities
Osteoclasts – bone
Mast cells
Microglia – brain
CELLS AND TISSUES OF IMMUNE SYSTEM - antigen presenting cells
Dendritic Cells
o Major cells for displaying protein antigens to naive T cells to initiate immune responses.
o Location: under epithelia, the most common entry site of antigens (Ag); interstitial of all tissues where Ag maybe produced
o Langerhans cells – immature dendritic cells within epidermis
o Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response
o Have 2 functionally distinct types: dendritic cells or interdigitating dendritic cells and follicular dendritic cells.
Dendritic Cells or Interdigitating Dendritic Cells
- Express high levels MHC Class II and T cell co-stimulatory molecules
- They capture and present antigens to T cells
- Reside in and under epithelia – strategically located to capture entering microbe (e.g., Langerhans cells)
- T cell zones of lymphoid tissues
- Interstitium of many non-lymphoid organs (e.g., heart and lungs)
- Plasmacytoid dendritic cells (subset of dendritic cells) resemble plasma cells and found in the blood and lymphoid organs; major source of antiviral cytokine type I interferon in response to many viruses.
Follicular Dendritic Cells
- Found in the germinal centers of lymphoid follicles in the spleen and lymph nodes.
- Have receptors for Fc tails of IgG molecules and for complement proteins
- Effectively trap antigens bound to antibodies and complement.
- They display antigens to activated B cells in lymphoid follicles and promote secondary antibody responses
- Not involved in capturing antigens for display to T cells.
CELLS AND TISSUES OF IMMUNE SYSTEM - Lymphoid Tissue
Generative organs (Primary)
o Where lymphocytes express antigen receptors and mature
o Organs involved – thymus and bone marrow
Peripheral lymphoid organs (Secondary)
o Where adaptive immune response develop
o Organs involved – lymph nodes, spleen, and mucosal, and cutaneous lymphoid tissues
HUMORAL IMMUNITY
B cell mediated via production of antibody
Often develops as a response to soluble antigens
B cells account for about 20% of the circulating lymphocytes
Immunoglobulin gene rearrangements allow tremendous diversity of responses to many antigens
Structure of an immunoglobulin molecule. There are 2 heavy (H) chains and 2 light (L) chains linked by disulfide bonds. Each heavy and light chain has a constant (C) and variable (V) region. It is the variable region in Fab portion that react with a specific antigen and give rise to the diversity of immunologic response. Immunoglobulin can attach via the Fc portion to a variety of cells with Fc receptors.
HUMORAL IMMUNITY - Major Mechanisms of B cell Activation
o T cell-independent
Polysaccharide and lipid antigens => multiple identical antigenic determinant (epitopes) that are able to engage several antigen receptor molecules on each B cell and initiate the process of B cell activation
o T cell-dependent
Globular protein antigens –> bind to many antigen receptors
CD4+ T cells => needed to have full response of B cells to protein antigens.
B cells => act as APCs => they ingest protein antigens, degrade them and display peptide bound to MHC Class II molecules for recognition of helper T cells => helper T cells express CD40L and secrete cytokines => activation of B cells
Humoral immune response combats microbes in different ways. Naïve B lymphocytes recognize antigens and under the influence of helper T cells and other stimuli, the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy chain class switching and affinity maturation, and some become long-lived memory cells. Antibodies of different heavy chain isotypes (classes) perform different effector functions.
HUMORAL IMMUNITY - antibody
o IgG and IgM – activate complement system through classical pathway => promotes phagocytosis and destruction of microbes
o IgA – mucosal tissue secretions and neutralization of microbes
o IgG – transported across the placenta; protection of the newborn => passive immunity
o IgE – opsonize helminthic parasites and functions with mast cells and eosinophils to kill them.
o IgD
CELLULAR IMMUNITY
T cell-mediated
No antibody involved, only cytokines; elicited by insoluble antigen – TB, cat scratch disease, fungal infections
Antigens and co-stimulators in peripheral lymphoid organs => activation of naive T lymphocytes => proliferation and differentiation into effector cells => these effector cells migrate to antigen present sites
Activated T lymphocytes => secrete soluble proteins (cytokines) for growth and differentiation factors for lymphocytes and other cells, and for communication between leukocytes
Cell-mediated immunity.
Naive T cells recognize MHC-associated antigens displayed on dendritic cells in lymph nodes. The T cells are activated to proliferate (under the influence of the cytokine IL-2) and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. Effector CD4+ T cells of the Th1 subset recognize the antigens of microbes ingested by phagocytes and activate the phagocytes to kill the microbes; Th17 effector cells enhance leukocyte recruitment and stimulate inflammation; Th2 cells activate eosinophils. CD8+ CTLs kill infected cells harboring microbes in the cytoplasm. Some activated T cells differentiate into long-lived memory cells. APC, antigen-presenting cells’ CTLs, cytotoxic T lymphocytes.
CELLULAR IMMUNITY
CD4+ Helper Lymphocytes
o Help B cells make antibody
o Help generate cytotoxic T cells
o Participate in delayed hypersensitivity reactions
o 60% of peripheral T lymphocytes
CD8+ Suppressor Lymphocytes
o Mainly cytotoxic
o 30% of circulating T lymphocytes
T CELL REACTIONS capable of tissue injury
o Delayed hypersensitivity
Type IV hypersensitivity
Initiated by CD4 T cells
Mechanism: CD4+ T cells secrete cytokines which lead to recruitment of other cells such as macrophages. These macrophages digest insoluble antigens as well as the surrounding tissues
B cells digest soluble antigen
T cells digest insoluble antigen
E.g. TB => caseous necrosis due to effect of CD4+ T cells
o Direct Cell Cytotoxicity mediated by cytotoxic CD8+ T cells
30% of circulating T lymphocytes
May help in the production of Cytotoxic T Lymphocytes
Greater amount of suppressor type than cytotoxic type - there are more CD8+ suppressor lymphocytes than cytotoxic T cells, though cytotoxic may contain CD8+
When they are counted, the CD8+ contribution comes from the CD8+ suppressor lymphocytes
T cell reactions capable of tissue injury
Participate in Direct Cell Cytotoxicity - cytotoxic T cells may also contain CD8+ receptors which can directly kill the antigen and somehow cause tissue injury
Ratio of CD4+ to CD8+ is usually 1:4; if the ratio decreases in favor of CD8+ it means that the CD4+ count is diminishing as seen in cases of HIV
CELLULAR IMMUNITY - T cell receptor (TCR)
Genetically programmed to recognize specific antigens
If genetic defect of TCR is present, there will be some organisms wandering around and they cannot be destroyed because specific TCR is absent.
They can rearrange their alpha and beta genes to respond to antigenic stimuli – adaptive response
Consists of a disulfide-linked heterodimer made up of an α and β polypeptide chain, each having a variable (antigenbinding) region and a constant region
Α β TCR recognizes peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells (APCs)
Each TCR is noncovalently linked to five polypeptide chains which form the CD3 and the ζ (zeta) chain dimer
CD3 and ζ proteins - invariant; involved in the transduction of the signals into the T-cell after the TCR has bound the antigen
γδ TCR - recognized peptides, lipids, and small molecules, without a requirement for display by MHC proteins; found on epithelial surfaces; γδ T cells are sentinels that protect against microbes that try to enter through the epithelia
Subsets of CD4+ effector T cells. In response to stimuli (mainly cytokines) present at the time of antigen recognition, naive CD4+ helper T cells may differentiate into populations of effector cells that produce distinct sets of cytokines and perform different functions. The types of immune reactions elicited by each subset, and its role in host defense and immunological diseases, are summarized.
Cytokines involved in innate immunity and inflammation:
major cytokines are TNF and IL-1 and a group of chemoattractant cytokines called chemokines, IL-12, IFN-gamma, IL-6, and IL-23 are some cytokines that also participate in the early innate immune response.
Cytokines that regulate lymphocyte responses and effector functions in adaptive immunity:
for proliferation and differentiation, IL-2 and IL-4; for activation of various effector cells, IFN-gamma => macrophage activation, and IL-5 => eosinophil activation. Major sources of these cytokines are CD4+ helper T cells.
Cytokines that stimulate hematopoiesis:
colonys-timulating factors (CSF) serve to increase the output of leukocytes from the bone marrow and to replenish leukocytes that are consumed during immune and inflammatory reactions.
**Interleukin is not produced by antibody; it is produced when there is T cell activation or cellular immune response
Effector functions of T lymphocytes
o Early response of CD4+ helper T cells => secretion of IL-2 and expression of high affinity receptors for IL-2 => IL-2 is a growth factor that acts on these T lymphocytes, stimulates proliferation, leading to an increase in the number of antigen-specific lymphocytes.
o Progeny of the expanded pool of T cells => different effector cells => different sets of cytokines => different functions
o Best defined subsets of CD4+ helper cells => Th1, Th2, and Th17
Th1 => produces IFN-gamma for macrophage activation and stimulation of B cells for antibody production.
Th2 => produce IL-4 for B cells stimulation => IgE-secreting plasma cells; produce IL-5 for eosinophil activation; and IL-13 for activation of mucus secretion of the mucosal epithelial cells and activation of macrophages to secrete growth factors.
Th17 => produce IL-17 for neutrophil recruitment and inflammation promotion.
CLASSES OF MHC/HLA The most intensely studied HLA genes are the nine so-called classical MHC genes. In humans, the MHC is divided into 3 regions: classes I, II and III. The A, B and C genes belong to MHC class I, whereas the six D genes belong to class II.
CLASSES OF MHC/HLA
Class I antigens: subsets A, B, and C
o Present on all nucleated cells (RBC or mature red cell is not of Class I antigen because it does not have nucleus)
o Encoded by several genes all clustered in the same region on chromosome 6
o Each gene has an unusually large number of alleles (alternate forms of gene that produce alternate forms of the protein). As a result, it is very rare for 2 individuals to have the same set of MHC molecules, which are collectively called a tissue type
o Tested for and detected by simple serologic assay
o “C” antigens unimportant (not usually used in diagnostics so you have to know only the A and B)
Number of alleles are present, and each person inherits one from each parent; thus, a person might be HLA typed as:
o A 5, 10
From 2017: HLA 5 may be inherited from the mother and 10 from the father. So there is that diversity (Fig.8). If your relative, say your brother who is the recipient, has a different inherited HLA from the parents (5 from mother & 10 from father), chances are there might be a great difference in the MHC typing and you will not be compatible.
o B 11, 41
From 2017: MHC-I / HLA-I proteins display antigens (i.e. protein fragments) that come from inside the cell
Example: viral proteins that are created inside a cell after it becomes infected would eventually get shown to T cells by MHC I proteins on the cell’s surface. They are vital component of viral immunity.
Class II antigens: in the D region of chromosome 6 (DR)
Each person inherits a pair of HLA-DP genes (DPA1 and DPB1, which encode α and β chains)
A couple of genes HLA-DQ (DQA1 and DQB1, for α and β chains)
One gene HLA-DRα (DRA1)
One or more genes HLA-DRβ
o Have a narrow distribution
o Mostly on mononuclear inflammatory cells. Occur on APCs: macrophages, dendritic cells and B cells which directly secrete antibody but do not react with the MHCs
o Detected by mixed lymphocyte assay
o MHC-II/HLA-II proteins show antigen that originates from outside the cell
o Example: some cells are able to gobble up bacteria and chew up its proteins. These cells are known as antigen presenting cells (APCs). They take that gobbled up bacterial protein and show it to T-cells on MHC-II proteins embedded in their cellular membranes
**REMEMBER: MHC I detected by simple serologic assay; MHC II detected by mixed leukocyte assay
HLA GENES and DISEASE
For complicated reasons specific HLA genes are linked to various autoimmune disorders
For example
A. B27: with ankylosing spondilytis, Psoriasis, Inflammatory Bowel Disease
B. B8: Grave’s disease, SLE
C. DR2: MS, SLE, Goodpasture’s disease
D. DR3: DM, SLE
E. DR4: RA, DM Type 1, Pemphigus vulgaris
F. DR5: Pernicious anemia, Hashimoto’s thyroiditis
G. DQ3: Alopecia areata
IMPORTANCE OF MHC/HLA
in transplantation
regulate some immune responses
Virus-infected cells with class I antigen are lysed by CD8+ cells that can recognize the virus-cell complex
Class II antigens help to induce CD4+ cells
Associated with a variety of diseases, such as HLA B27 with ankylosing spondylitis, or HLA DR 2, DR3, and DR4 with autoimmune diseases
HYPERSENSITIVITY
Hypersensitivity reactions imply an excessive response to an antigenic stimulus. General concepts are:
Both exogenous and endogenous antigens can elicit a hypersensitivity response
Diseases occurring as a result of hypersensitivity response are often associated with particular susceptibility genes (e.g., HLA).
May be due an imbalance between immune effector mechanisms and control mechanisms that normally limit immune responses
- TYPE I HYPERSENSITIVITY (Anaphylaxis)
- TYPE II HYPERSENSITIVITY (Antibody-Mediated Hypersensitivity)
- TYPE III HYPERSENSITIVITY (Immune Complex Disease)
- TYPE IV HYPERSENSITIVITY (Delayed Hypersensitivity)
HYPERSENSITIVITY - TYPE I HYPERSENSITIVITY
Anaphylaxis:
o Prior sensitization
o Promote mast cell proliferation and plasma cell production of IgE.. The IgE becomes bound to mast cells in places such as the respiratory tract mucosa.
o Reexposure to same allergen results in mast cell degranulation
o Release of primary mediators such as histamine, serotonin causes vasodilation, bronchoconstriction
o Release of secondary mediators (such as leukotrienes, prostaglandin, bradykinins)
o Inflammatory cell infiltrates
Prior Sensitization. There must be a primer or a first exposure for you to develop a reaction. On the 2nd time, there is now bridging which is a critical stage in hypersensitivity type I, once there is bridging of the true antibody IgE with the antigen, there is mast cell degranulation of serotonin, histamine, leukotrienes, prostaglandin,and bradykinin.
*If asked in the exam, what is the event that is a prerequisite in mast cell degranulation of inflammatory substances? Bridging of IgE with an Ag, which leads to release of inflammatory substances.
HYPERSENSITIVITY - TYPE I HYPERSENSITIVITY
Two forms of anaphylaxis:
Systemic:
o It typically follows a parenteral or oral administration of foreign bodies
o Immediate reaction
o Symptoms include acute asthma, laryngeal edema, diarrhea, urticaria, shock (Anaphylactic shock)
o Ex: Bee sting, Anaphylaxis, Hay fever, Food allergies, Asthma
Local anaphylaxis (Atopy):
Easily sensitized to allergens that cause a localized reaction when inhaled or ingested
Ex. Pollen, dust, animal fur
o Food allergies
o Urticaria or Hives
o Asthma
o Produces Hay fever/ allergic rhinitis (Ragweed pollen)
o Wheal reaction: local area to erythema and edema due to intradermal injection of antigen in sensitized individual.
HYPERSENSITIVITY - TYPE I HYPERSENSITIVITY
Local anaphylaxis (Atopy). A form of localized anaphylaxis with type I hypersensitivity occurs with “hay fever” when allergens in plant pollens contact IgE bound to mast cells, causing them to release their granules containing mediators such as histamine that promote vasodilation and edema. Beneath the nasal mucosa at the left, eosinophils have been attracted. The plasma cells seen here have collected due to the chronic nature of the antigenic stimulation.
REMEMBER:
What is the antibody involved? IgE
What is the event that causes degranulation? Bridging of antigen to antibody
What cell is involved? Mast cell
What are the substances involved? Serotonin, histamine, leukotrienes, prostaglandin and bradykinin
HYPERSENSITIVITY - TYPE II HYPERSENSITIVITY
Known as Antibody-Mediated Hypersensitivity
These reactions are dependent on complement, consisting of three mechanisms
- Complement Classical Pathway
- Antibody-dependent cell-mediated cytotoxicity (ADCC)
- Antireceptor antibodies
HYPERSENSITIVITY - TYPE II HYPERSENSITIVITY
Three Mechanisms of Type II Hypersensitivity: Complement Classical Pathway
o Antibodies which are produced by the body’s immune response bind the antigens on the body’s own cell surfaces; can be on cells as circulating RBCs or extracellular materials like the basement membrane
o This results to Ag-Ab complexes which activate the classical complement pathway. The end result is cell lysis and extracellular tissue damage
Examples:
Transfusion reactions: RBC’s or serum is incompatible
Autoimmune hemolytic anemia: antibodies are produced against the patient’s own RBC’s
Erythroblastosis fetalis (know): results from rhesus incompatibility between Rh-negative mother and Rh-positive fetus.
- Elevated Rh Ab titers
- Many immature RBCs in blood
- Hyperbilirubinemia from RBC breakdown = jaundice
- First baby – OK, because IgM cannot cross the placenta, after that IgG takes over
- Progressive anemia, ischemia, death
- Brain damage from bilirubin: Kernicterus
- Prevention: Rh (-) mother gets anti-D immunoglobulin after birth of first child (covers antigenic sites on baby’s RBCs in mother’s blood)
- Rx: phototherapy of baby (breaks bilirubin)
Goodpasture’s Syndrome (know): antibodies attack alveoli and the glomerular basement membrane; lead to complement cascade
- An immunofluorescence assay with antibody (Ab) to IgG in a patient with this disease will exhibit a linear pattern because the Ab is directed against the entire glomerular basement membrane (antiglomerular basement membrane Ab)
Hyperacute rejection
HYPERSENSITIVITY - TYPE II HYPERSENSITIVITY
Three Mechanisms of Type II Hypersensitivity: Antibody-dependent cell-mediated cytotoxicity (ADCC)
o Low concentrations of IgG or IgE coat target cells, which signal inflammatory cells; such as NK Cells, monocytes, and granulocytes. These bind to immunoglobulin Fc receptors, which lyse target cells. Note that they are not phagocytosed.
o Macrophages with Fc receptors are able to recognize targeted cells coated with antibodies. Macrophages then destroy these cells through proteases.
Examples:
Transplant rejection
Immune reactions against: neoplasms, parasites
HYPERSENSITIVITY - TYPE II HYPERSENSITIVITY
Three Mechanisms of Type II Hypersensitivity: Antireceptor antibodies
o Receptors on target cells are destroyed by complement mediated factors; due to IgG antibody directed towards target cells.
Examples:
Myasthenia gravis: Ach receptor antibody
Grave’s Disease (thyrotoxicosis): anti-TSH receptor antibody
Pernicious anemia: anti-parietal cell antibody
HYPERSENSITIVITY - TYPE II HYPERSENSITIVITY
Clinical Manifestations
Autoimmune hemolytic anemia
Agranulocytosis
Thrombocytopenia
Pemphigus Vulgaris – chronic blistering skin disease with skin lesions that are rarely pruritic
Pehphigoid – a rare autoimmune blistering skin disease without skin lesion
HYPERSENSITIVITY - TYPE III HYPERSENSITIVITY
Immune Complex Disease: Immune (Ag-Ab) complexes, which are either formed intra- or extravascularly, mediate Eosinophil complement activation (alternate pathway) and promote tissue damage.
C3b acts as an opsonin that promotes phagocytosis via neutrophils, which then release lysosomal enzymes.
C5a acts as a chemoattractant and brings in neutrophils.
As this reaction progresses, serum complement is reduced due to system use.
There are two types based on the location of immune complex deposition:
o Systemic immune complex disease
o Local Immune Complex Disease (“Arthus Reaction”)
HYPERSENSITIVITY - TYPE III HYPERSENSITIVITY
types based on the location of immune complex deposition: Systemic immune complex disease
Ag-Ab complexes form in the circulatory system (intravascular formation) => deposited in tissues, typically near basement membranes (blood vessels, glomeruli, skin, joints, pleura, and pericardium). Larger immune complexes are quickly phagocytosed by macrophages, however, some small to intermediate complexes formed with antigen excess may escape removal leading to: Glomerulonephritis, serum sickness, vasculitis
Could result from the administration of large amount of foreign serum
Steps
- Ag-Ab complex formation and deposition
- Microthrombi formation
- Ischemia
- Release of lysosomal enzymes
- Necrosis
Damage:
- Acute (single alrge dose of Ag exposure)
Acute serum sickness
Poststreptococcal glomerulonephritis
- Chronic (persistent/repeated Ag exposure)
Systemic lupus erythematosus
Rheumatoid arthritis
Membranous glomerulonephritis
HYPERSENSITIVITY - TYPE III HYPERSENSITIVITY
types based on the location of immune complex deposition: Local Immune Complex Disease (“Arthus Reaction”)
A localized area of tissue necrosis arising resulting from acute immune compex vasculitis, usually elicited in the skin.
Local formation and deposition of Ag-Ab complexes
Can be produced by a local injection of an antigen to an immunized individual. Plays a role in the development of hypersensitivity pneumonitis (farmer’s lung).
Large immune complexes deposition => complement and coagulation cascades activation and platelets aggregation lead to fibrinoid necrosis
Common clinical findings
o Fever
o Urticaria “hives”
o Arthralgia – joint pain
o Lymphadenopathy
o Proteinuria
HYPERSENSITIVITY - TYPE IV HYPERSENSITIVITY
Delayed Hypersensitivity: Mediated by sensitized CD4+ T lymphocytes which process antigens in association with class II HLA molecules and release lymphokines. Lymphokines promote a reaction mediated by macrophages in hours, but peaks in 2 to 3 days
Examples:
Granulomatous diseases (mycobacteria, fungi)
Tuberculin skin reactions
Transplant rejection
Contact dermatitis
Two Types:
Delayed-Type Hypersensitivity (DTH)
Cytotoxic T lymphocyte (CTL) mediated responses
HYPERSENSITIVITY - TYPE IV HYPERSENSITIVITY
2 types:
Delayed-Type Hypersensitivity (DTH):
o Principal pattern of response in TB, fungi, protozoa & parasites, graft rejection and tumor immunity
o Mediated by CD4 cells, whose induction is facilitated by IL-12 secreted by macrophages, in association with MHC II
o Cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages.
o With persistence of non-degradable antigens, the initial non-specific of T cells and macrophages is replaced by collections of macrophages that transform into epithelioid cells forming local granuloma. Hence, a granuloma is a special form of DTH
Cytotoxic T lymphocyte (CTL) mediated responses:
o CD8+ T cells generated => lyse specific cells.
o Role of Class I HLA molecules: CTL bind MHC 1 of cells, kill them, enacting cell mediated immune response
Reactions with this mode:
Neoplastic cell lysis
Transplant rejection
Virus-infected cell lysis
o Mechanism of CTL Killing
Perforin-granzyme-dependent killing: perforin and granzyme are soluble mediators of the CTLs that induce apoptosis of the target cells.
Fas-fas ligand-dependent killing: activated CTLs express Fas ligand (a molecule with homology to TNF) which binds to Fas on target cells that leads to apoptosis.
TRANSPLANT REJECTION
Two Important Pathologies in Transplantation:
Rejection - recipient rejects donor tissue
Graft vs Host (GVH) Disease - immunodeficient recipient cannot reject donor tissue and produces adverse reactions on the recipient
Immunologic Mechanisms
Histocompatibility Lymphocytic Antigen (HLA) system
>Key Factor
o MHC determining factor in chromosome 6
o Reactions mediated by either T lymphocytes or antibody.
o Major types of hypersensitivity reactions involved: type II and type IV
The ABO system
o Best characterized as the major blood group antigens
o Expressed on all cells except in the central nervous system. Thus, matching for ABO compatibility is important for transplantation.
T-cell Mediated Reactions
o Either:
- CD4+ cells generating delayed hypersensitivity reactions after recognizing foreign HLA class II (DR) antigens
- Cytotoxic CD8+ cells recognizing foreign HLA class I (A, B, or C) antigens. The donor tissue or donor lymphocytes within the transplanted tissue carry the offending HLA antigens.
Antibody mediated reactions
o Mediated through:
- Complement-mediated cytotoxicity
- Antibody-dependent cytotoxicity (ADCC)
- Immune complexes
ORGAN SYSTEM PATHOLOGY
4 Classic Modes of Renal Transplant Rejection
- Hyperacute Rejection
- Acute Cellular Rejection
- Acute Vascular Rejection
- Chronic Rejection
ORGAN SYSTEM PATHOLOGY - Hyperacute Rejection
Occurs within minutes or hours after transplantation.
A hyperacutely-rejecting kidney rapidly becomes cyanotic, mottled, and flaccid; may excrete a few drops of bloody urine.
Preformed antibody causing immediate (minutes to hours) vascular injury via ADCC
o Immunoglobulin and complement are deposited in the vessel wall, causing endothelial injury and fibrin-platelet thrombi.
o Neutrophils rapidly accumulate within arterioles, glomeruli, and peritubular capillaries.
o As these changes become diffuse and intense, the glomeruli undergo thrombotic occlusion of the capillaries, and fibrinoid necrosis occurs in arterial walls.
o The kidney cortex then undergoes outright necrosis (infarction), and such nonfunctioning kidneys have to be removed.
**
Q: What is the mechanism of hyperacute rejection?
A: Presence of preformed antibody
ORGAN SYSTEM PATHOLOGY - Acute Cellular Rejection
Most commonly seen within the initial months after transplantation and is heralded by clinical and biochemical signs of renal failure.
Histologically, there may be extensive interstitial mononuclear cell infiltration and edema as well as mild interstitial hemorrhage.
Cellular infiltrates with both CD4+ and CD8+ T cells.
Occurrence is sometimes within days, usually within months, or sometimes years later when immunosuppressive therapy is discontinued.
Primarily T cell mediated cytotoxic damage
Density of the infiltrate and extent of parenchymal damage determine severity
Glomerular and peritubular capillaries contain large numbers of mononuclear cells that may also invade the tubules, causing focal tubular necrosis.
CD8+ T cells may injure vascular endothelial cells, causing endothelitis.
Hyperacute: Occurs only in the first few hours after transplantation
Acute cellular: Can occur any time after transplantation
At high magnification, the lymphocytes and plasma cells are seen around a renal tubule in a renal transplant patient with acute cellular rejection. This type of rejection can occur at any time following transplantation when immunosuppression is diminished. This is treated by administering cyclosporine and other immunosuppressive agents.
The immunofluorescence pattern with acute tubulointerstitial renal transplant rejection is shown here, in which immune deposits occur between glomeruli in the interstitium. Both type II and type IV immune hypersensitivity reactions contribute to this rejection reaction. Encircled are the immune complexes which are not continuous
ORGAN SYSTEM PATHOLOGY - Acute Vascular Rejection
Rejection primarily at the vasculature of the graft
3 general stages:
o Early: Subendothelial inflammation and hypertrophy of endothelium
o Intermediate: Moderate intimal proliferation with more significant wall inflammation
o Severe: Significant fibrinoid necrosis and intimal proliferation.
Both cell mediated and humoral immunity involvement
ORGAN SYSTEM PATHOLOGY - Chronic Rejection
Emerged as an important cause of graft failure
Intimal fibrosis with vascular thickening Ischemic changes.
Mononuclear infiltrates with prominent plasma cells.
Both T-cell and humoral mechanisms leads to increasing intimal fibrosis and ischemia.
Presented clinically with progressive renal failure manifested by rise in serum creatinine over a period of 4 to 6 months.
Dominated by vascular changes, interstitial fibrosis, tubular atrophy, and shrinkage of the renal parenchyma.
Glomeruli may show scarring with duplication of basement membranes Chronic Transplant Glomerulopathy
At high magnification, the renal arteries with chronic vascular rejection are markedly thickened and fibrotic. There is interstitial fibrosis and chronic inflammation. Such chronic rejection usually occurs slowly over several months to years following transplantation. This form of rejection, unlike acute cellular rejection, is difficult to treat. The arrow points to the occluded lumen.
GRAFT VS. HOST DISEASES
An immune reaction of the host against a graft (e.g. organ)
GVH occurs in immunologically challenged patients wherein donor tissue contains antigen that cannot be rejected by the patient
2 phases
1. Acute: Cell necrosis of skin and GI tract, cholestasis
2. Chronic: Over 100 days post-transplant; manifested as dermal fibrosis, desquamative esophagitis, portal tract fibrosis => Cholestasis
In bone marrow transplant, GVH is the greatest problem, however, in cases of bone marrow malignancy transplant, graft vs. tumor effect is therapeutic
Immunodeficiency is a frequent complication of bone marrow transplantation.
The immunologically incompetent recipient cannot reject the graft, T cells present in the donor recognize the recipient tissue as “foreign” and react against it resulting in activation of both CD4+ (DTH) and CD8+ T cells (CTL)
GRAFT VS. HOST DISEASES
Graft versus host disease (GVHD) also leads to marked cholestasis in the liver, seen here as large collections of yellow-green bile pigment within the bile canaliculi.
Microscopically, graft versus host disease (GVHD) is one of the best examples of a process called “apoptosis” (black arrow) or single cell necrosis. There is vacuolization (encircled) and dissolution of epidermal cells along the basal layer, along with lymphocytes. At the arrow is a rounded pink apoptotic body.
GRAFT VS. HOST DISEASES - Liver Transplants
Human leukocyte antigen (HLA ) is less important than simple matching of organ size (since most of these are done in children)
Two modes of rejection:
1. Acute Rejection
This is characterized by infiltration of a mixed population of inflammatory cells including eosinophils into the portal tracts, bile duct, which cause hepatocyte injury and endothelitis.
Mixed inflammatory portal and central vein infiltrates.
- Chronic Rejection:
Continued inflammation, portal fibrosis, arteriolar thickening, and bile ductular necrosis
Severe obliterative arteritis of small and larger arterial vessels (arteriopathy) results in ischemic changes in the liver parenchyma
Bile ducts are progressively destroyed, because of either direct immunological attack or obliteration of their arterial supply, resulting in loss of the graft.
GRAFT VS. HOST DISEASES - Heart Transplants
HLA is less important than simple matching of organ size. Immunosuppressive therapy is carefully monitored in relationship to signs of rejection on endomyocardial biopsy
Two modes of rejection:
1. Acute Cellular Rejection:
Lymphocytic infiltrates
Possible myocardial fiber necrosis
2. Acute Vascular Rejection:
Immunoglobulin deposition in small arteries => Vasculitis
GRAFT VS. HOST DISEASES - Heart Transplants
This is acute vascular rejection in a heart transplant. The inflammatory reaction consists mostly of lymphocytes and is seen mainly around small arteries (vasculitis). Such a reaction can occur when the dose of immunosuppressive drugs is decreased in the months following transplantation. Increasing immunosuppressive therapy in these patients is not as effective as for acute cellular rejection
GRAFT VS. HOST DISEASES - Heart Transplants
By immunofluorescence, antibody to IgG is seen highlighting the vascular walls in this heart with acute vascular rejection.
GRAFT VS. HOST DISEASES - Bone Marrow Transplants
Chemotherapy agents used to prepare patient for marrow transplantation may result in hepatic veno-occlusive disease in the weeks following transplantation
AUTOIMMUNE DISEASES
A condition whereby the own body is not recognized as “self” by the immune system
“Connective tissue” disorders because many are manifested in a variety of tissues
Hypersensitivity reactions involved in autoimmunity:
o Primarily types II and III
o Can also be present in type IV reactions
Mechanisms proposed for development of autoimmunity include:
o Bypass of CD4+ T-cell tolerance of “self” antigens by:
Complex of antigen with a hapten (such as a drug or infectious agent) or infectious degradation of an antigen
Cross-reaction with a hapten on an infectious agent that is similar to tissue proteins – classic for poststreptococcal glomerulonephritis and rheumatic heart disease
Direct activation of B-cells via bacterial endotoxin and via Epstein-Barr virus receptors on B-cells
Idiotype bypass through ligand mimicry, as seen in antireceptor antibody mediated disease, and cross-reactivity with infectious agents
T-suppressor/helper imbalance
Emergence of a sequestered antigen through tissue trauma or inflammatory destruction. e.g. lens crystalline of eye, spermatozoa in testis, and myelin in CNS
AUTOIMMUNE DISEASES - Types of Antinuclear Antibodies (ANA)
Seen in many autoimmune diseases but not diagnostic of any
In general, the higher the titer, the worse the disease
Characteristic fluorescent staining patterns for ANA:
o Homogenous (diffuse) – not very specific for anything
o Rim – may be indicative of anti-double stranded DNA, seen in SLE
o Speckled – indicative of antibody to extractable nuclear antigens, often seen in MCTD
o Nucleolar – antibody to nucleolar RNA, seen often in PSS
o Centromere – antibody to centromeric protein, seen in CREST syndrome
AUTOIMMUNE DISEASES - Types of Antinuclear Antibodies (ANA)
Screening for autoimmune diseases is often performed with the antinuclear antibody (ANA) test in which patient serum is incubated with a tissue substrate to which any autoantibodies to nuclear antigens will bind. Then, a fluorosceinated antibody is added and the tissue is observed under fluorescence microscopy to see if staining is present. Seen here is the typical “homogenous” pattern of nuclear staining of a positive ANA.
Sometimes when performing the ANA test, the substrate cells demonstrate particular patterns of staining. This is the so-called “rim” pattern that is more characteristic of systemic lupus erythematosus (SLE) than other autoimmune diseases.
These are Crithidia organisms, whose sole purpose for existence is to serve as a substrate for the double stranded DNA test. Here the little critters have brightly fluorescing kinetoplasts indicative of a positive test. A positive double stranded DNA test strongly suggests a diagnosis of SLE.
Autoantibodies and associated diseases
AUTOIMMUNE DISEASES
- Systemic Lupus Erythematosus (SLE)
- Discoid lupus erythematosus (DLE)
- Mixed Connective Tissue Disease (MCTD)
- Scleroderma (Progressive Systemic Sclerosis, PSS)
- Polymyositis-Dermatomyositis
- Sjogren’s Syndrome
AUTOIMMUNE DISEASES - Systemic Lupus Erythematosus (SLE)
Suggestive serologic and clinical findings (must have 4/11 to be diagnosed as SLE):
o Skin rash – malar or discoid
o Sensitivity to light (photodermatitis)
o Serositis – inflammation of serosal surfaces along with effusions
o Glomerulonephritis – the worst problem with SLE
o Cytopenias – anemia, leukopenia, thrombocytopenia
o Antinuclear antibody – rim pattern, anti dsDNA, anti-Smith autoantibodies (most specific for SLE)
o Arthralgias, myalgias
o Vasculitis: CNS, skin, kidney, etc
o Decreased serum complement: especially C1q
o Thrombosis: arteries or veins
o Genetic factors
Tends to run in families
Association with HLA Dr-2 and Dr-3
More common in young women (especially African-American)
o Drugs can produce “drug-induced” SLE
List includes procainamide, hydralazine, isoniazid, d-penicillamine
AUTOIMMUNE DISEASES - Systemic Lupus Erythematosus (SLE)
Histologically, the skin of a patient with SLE may demonstrate a vasculitis and dermal chronic inflammatory infiltrates, as seen here. Vasculitis with autoimmune disease (often related to deposition of antigen-antibody complexes) can occur in many different organs and can lead to the often confusing signs and symptoms of patients with rheumatic diseases.
Here is a more severe inflammatory skin infiltrate in the upper dermis of a patient with SLE in which the basal layer of epidermis is undergoing vacuolization and dissolution. There is purpura with RBCs extravasated into the upper dermis (which are the reasons for the rash).
AUTOIMMUNE DISEASES - Systemic Lupus Erythematosus (SLE)
Here is another immunofluorescence staining pattern with antibody to IgG showing evidence for immune complexes at the dermal-epidermal junction. If such a pattern is seen only in skin involved by a rash, then the pattern is more characteristic for DLE, but if this pattern appears even in skin uninvolved by a rash, then SLE may underlie this phenomenon.
AUTOIMMUNE DISEASES - Systemic Lupus Erythematosus (SLE)
There is vascular thrombosis in the dermis of the skin in this patient with antiphospholipid syndrome (APS). This syndrome results from presence of autoantibodies directed against anionic phospholipids, such as cardiolipin. This syndrome can occur in patients with SLE, and the antibody interferes with coagulation assays, giving it the name “lupus anticoagulant.” However, in vivo, patients have a hypercoagulable state with recurrent arterial and venous thromboses. In pregnancy, APS can lead to fetal loss.
The periarteriolar fibrosis (“onion skinning”) seen in the spleen in patients with SLE at autopsy is quite striking, though of no major clinical consequence. This results from vasculitis.
AUTOIMMUNE DISEASES - Systemic Lupus Erythematosus (SLE)
One of the feared complications of the autoimmune diseases is renal failure. This is most likely to occur with SLE and the diffuse form of scleroderma. Here is a glomerulus in which the capillary loops are markedly pink and thickened such that capillary lumens are hard to see. This is characteristic for lupus nephritis.
Here is a glomerulus with thickened pink capillary loops, the so-called “wire loops”, in a patient with lupus nephritis. The surrounding renal tubules are unremarkable
AUTOIMMUNE DISEASES - Mixed Connective Tissue Disease (MCTD)
A waterbasket category for patients who do not clearly fit into other categories
There are features similar to SLE, scleroderma, and polymyositis
Most patients are middle aged females
Characteristic feature is a speckled ANA pattern
AUTOIMMUNE DISEASES - Scleroderma (Progressive Systemic Sclerosis, PSS)
Excessive fibrosis in various tissues from collagen deposition by activated fibroblasts
About 75% of cases are women, mostly middle aged
Antinucleolar antibodies, esp. Scl-70 are very specific
Patterns of disease include:
o Limited scleroderma, or CREST syndrome: the benign form of PSS, serologically suggested by the presence of anti-centromere antibody
C = Calcinosis in skin and elsewhere
R = Raynaud’s phenomenon, sensitivity to cold
E = Esophageal dysmotility from submucosal fibrosis
S = Sclerodactyly from dermal fibrosis
T = Telangiectasias
o Diffuse scleroderma: worst form
Scl-70 (anti-DNA topoisomerase I) antibody specific for this form
Findings:
- CREST
- Renal arterial intimal thickening and proliferation (hyperplastic arteriolosclerosis) leading to malignant hypertension with arterial fibrinoid necrosis, thrombosis, and renal infarction. Half of patients die from renal disease
- Lungs: diffuse alveolar fibrosis leading to honeycomb fibrosis
- Morphea: skin fibrosis
AUTOIMMUNE DISEASES - Scleroderma (Progressive Systemic Sclerosis, PSS)
At low magnification, there is a greater amount and depth of dermal collagen, leading to the decrease in elasticity. Though scleroderma (systemic sclerosis) is an autoimmune disease, the main microscopic feature is fibrosis, and chronic inflammatory cell infiltrates are sparse, unlike SLE.
At high magnification, the dermis is expanded by dense collagenous fibrosis in a patient with systemic sclerosis. Immunofluorescence staining of the skin is not helpful with scleroderma, since immune complex deposition is not a prominent feature of this disease
AUTOIMMUNE DISEASES - Polymyositis-Dermatomyositis
Symmetrical inflammation of skeletal muscle with weakness. Sometimes associated with skin rash (dermatomyositis: vasculitis in muscle and skin due to Ag-Ab complex deposition)
Associated Ab is against nuclear antigen PMI and JO-I’s are very specific
“heliotropic rash”: purplish red tint on upper eyelids pathognomonic
Seen mostly in women ages 40-60, ages 5-15
Inflammation mainly mediated by cytotoxic CD8 cells
Some adults (10-20%) develop cancer
AUTOIMMUNE DISEASES - Sjogren’s Syndrome
dry eyes, dry mouth: lacrimal and salivary gland involvement by lymphocytic infiltration, fibrosis, and destruction mediated by CD4+ cells helping antibody production; anti-SS-A and anti-SS-B are the most specific.
Involves type II and IV hypersensitivity
Predisposed to lymphoma
Most patients are middle to older age women.
Mikulicz’s syndrome (umbrella term): Lacrimal and salivary gland inflammation of any cause (including Sjogren’s)
PRIMARY IMMUNODEFICIENCY SYNDROMES
- X-linked Agammaglobulinemia
- Common Variable Immunodeficiency (CVID)
- DiGeorge Syndrome
- Severe Combined Immunodeficiency (SCID)
- Wiskott-Aldrich Syndrome
- Ataxia-Telangiesctasia
- Selective IgA Deficiency
- Other Primary Immunodeficiency Disorders
PRIMARY IMMUNODEFICIENCY SYNDROMES - X-linked Agammaglobulinemia
Congenital agammaglobulinemia (Bruton’s Disease)
genetic defect on the long arm of X chromosome,
males primarily affected (inheritance occurs in an X-linked recessive pattern).
The mutations affect production of a tyrosine kinase (Bruton tyrosine kinase, or btk) active in early pre-B cells which diminishes their maturation and leads to virtual absence of all immunoglobulin classes.
Infants are observed to have multiple infections with bacterial organisms (Hemophilus, Staphylococcus), particularly in skin and lung.
Agammaglobulinemia is the result of absent B-cells, but T-cell mediated immunity is intact.
If affected persons survive, many will develop autoimmune diseases.
PRIMARY IMMUNODEFICIENCY SYNDROMES - Common Variable Immunodeficiency (CVID)
Heterogenous group of disorders
incidence : 1 per 100,000
Involves both humoral and cell mediated immunity.
Normal numbers of circulating B lymphocytes, with impaired secretion of one or more immunoglobulin isotypes, usually IgG or IgA.
Selective abnormality of T cell activation, as demonstrated by decreased synthesis of interleukins (IL 2, 4, and 5)
Patients may have impaired gastrointestinal mucosal immunity.
Variants:
o Either a decrease in CD4 cells or an increase in CD8 cells.
o Presence of T and B lymphocyte autoantibodies.
At least two of the three main serum immunoglobulin isotypes are decreased.
Persons are prone to recurrent bacterial infections, particularly sinusitis, bronchitis, pneumonia, bronchiectasis, and otitis.
Bordatella pertussis infections occur in childhood.
Viral infections are uncommon, though recurrent herpes simplex with eventual herpes zoster is an exception.
Giardiasis is common.
Hypoplastic germinal centers and other B cell areas, no plasma cells
Half are diagnosed before age 21, in some, complications do not develop until adolescence or adulthood.
Increased incidence of autoimmune diseases: hemolytic anemia, thrombocytopenia, and pernicious anemia.
In about two thirds of cases, normal numbers of circulating B lymphocytes are present.
Decrease in immunoglobulins, generally in all classes, more often IgG and IgA, sometimes only of IgG.
PRIMARY IMMUNODEFICIENCY SYNDROMES - DiGeorge Syndrome
Field defect of third and fourth pharyngeal pouch development in utero during organogenesis in the first trimester of pregnancy.
Subclassification:
o Complete: almost total absence of thymic tissue
o Partial: only a decrease in thymic tissue
A specific deletion on the long arm of chromosome 22.
Anatomic structures that may be aplastic or hypoplastic: thymus, parathyroid, great vessels, and esophagus.
Complete DiGeorge syndrome: normal levels of circulating immunoglobulin, though in some cases serum IgE is increased and IgA decreased.
Markedly decreased numbers of circulating T lymphocytes: susceptible to fungal and viral infections.
Children with partial DiGeorge syndrome
o Slight decrease in peripheral T lymphocytes
o Increased infections, but with less frequency and with less severity than children with the complete form.
o Accompanying aplasia of parathyroid glands: life-threatening hypocalcemia that may appear soon after birth.
PRIMARY IMMUNODEFICIENCY SYNDROMES -Severe Combined Immunodeficiency (SCID)
Failure in development of both humoral and cell-mediated immunity
The major variants of SCID include:
o An X-linked form:
Mutation on the long arm of the X chromosome defective gamma chain of the IL-2 receptor (cytokine receptor) renders early lymphocytes incapable of normal differentiation and development to functional T and B cells in response to growth factors
Accounts for about 60% of cases
o Autosomal recessive inheritance
Lack of adenosine deaminase (ADA) leads to about 35 to 40% of cases
ADA enzyme is involved in purine metabolism: deficiency results in production of metabolites toxic to lymphocytes
Greater decrease in cell mediated immunity than in humoral immunity
Very little serum IgG and virtually no IgM or IgA. Infants develop Candida skin rashes and thrush, persistent diarrhea, severe respiratory tract infections with Pneumocystis carinii , Pseudomonas soon after birth, and failure to thrive after 3 months of age
PRIMARY IMMUNODEFICIENCY SYNDROMES - Wiskott-Aldrich Syndrome
X-linked recessive pattern
Defective gene located on the short arm of the X chromosome (Xp11.23).
Immunodeficiency accompanied by thrombocytopenia and eczema.
Circulating platelets markedly decreased
T lymphocytes exhibit:
cytoskeletal disorganization
loss of microvilli by electron microscopy,
express little CD43 by immunohistochemical staining.
Usually with a normal level of serum IgG, decrease in IgM, often with an increase in both IgA and IgE.
Disease in early childhood: recurrent bacterial infections, particularly to encapsulated bacteria : Streptococcus pneumoniae, pneumonia, meningitis, septicemia.
Failure of T lymphocyte function may predispose to recurrent herpetic infections and Pneumocystis carinii pneumonia.
Bleeding problem may result from the severe thrombocytopenia.
PRIMARY IMMUNODEFICIENCY SYNDROMES - Ataxia-Telangiesctasia
Genetic defect present on the long arm of chromosome 11
Predisposes to chromosome breakage and rearrangement, particularly on chromosomes 7 and 14, high risk for neoplasia, marked sensitivity to radiation.
Rare and has an autosomal recessive pattern of inheritance.
Triad of progressive cerebellar ataxia, mucocutaneous telangiectasias, and recurrent respiratory tract infections with a variety of bacterial and fungal organisms.
Immunoglobulin deficiencies, particularly IgA and/or IgE, may be present, though serum IgM is usually elevated.
Symptoms usually begin between 9 months and 2 years of age.
PRIMARY IMMUNODEFICIENCY SYNDROMES - Selective IgA Deficiency
About 1 in 600 persons of European descent lack circulating IgA as well as secretory IgA.
Results from failure of the IgA type of B lymphocytes to transform into plasma cells capable of producing IgA or from impaired survival of IgA producing plasma cells.
Some affected patients at increased risk for respiratory, gastrointestinal (diarrhea), and urinary tract infections, most often bacterial.
More severely affected persons may even have a sprue-like illness with malabsorbtion.
Atopy, as demonstrated by asthma, can be present.
Concomitant autoimmune diseases, particularly systemic lupus erythematosus and rheumatoid arthritis,
About half of IgA deficient persons develop anti-IgA antibodies of the IgE type, so that transfusion of blood products containing serum with normal IgA levels leads to severe systemic anaphylaxis.
PRIMARY IMMUNODEFICIENCY SYNDROMES - Other Primary Immunodeficiency Disorders
Deficiencies of other components of the immune system are uncommon. Some of the best known are:
o Complement component deficiencies
C2 deficiency carries a risk for development of autoimmune disease
C3 deficiency is associated with recurrent bacterial infections
o Chediak-Higashi syndrome
A rare autosomal recessive disorder in which peripheral blood neutrophils, monocytes, and lymphocytes contain giant cytoplasmic granules
patients have leukopenia, making them susceptible to bacterial and fungal infections of skin, mucous membranes, and respiratory tract
o Chronic granulomatous disease
neutrophils and monocytes lack the enzyme NADPH oxidase which is needed to generate intracellular oxidants that destroy phagocytosed infectious organisms, particularly catalase-positive agents such as Staphylococcus aureus, Candida, and Aspergillus,
chronic infections are common
ACUTE IMMUNODEFICIENCY SYNDROME
Hallmark of AIDS: Profound immune deficiency, primarily affecting cell-mediated immunity
Characterized by:
o Profound suppression of T cell mediated immunity
o Opportunistic infection
o Secondary neoplasm
o Neurologic diseases
Transmission of HIV
Sexual contact: Predominant mode of transmission
Parenteral inoculation
o IV drug users (sharing of needles)
o Hemophiliacs who received the factor VIII concentrates
o Random recipients of blood transfusion
Vertical transmission
o 90% of children with AIDS have an HIV infected mother
o Infected mothers can transmit infection to their offspring in 3 routes:
In utero by transplacental spread
During delivery through infected birth canal
After birth by ingestion of breast milk
5 major Risks Group in USA
o Homosexual/Bisexual men: 42%
o Intravenous drug users: 25%
o Hemophiliacs: 0.5%
o Blood/component recipients: 1% of all patients excluding hemophiliacs
Other risk Groups patients
o Medical and paramedical professionals
o OFW
o Commercial Sex Workers
o Sea Men
ACUTE IMMUNODEFICIENCY SYNDROME - Pathogenesis
Etiology: Properties of HIV
HIV is a non-transforming human retrovirus belonging to the lentivirus family
o HIV-1: Associated with AIDS commonly found in the US, Europe and Central Africa.
o HIV-2 : India and West Africa
Two Major Targets of HIV Infections
Immune system
o T Helper lymphocytes
o Macrophage
o Monocytes
CNS
o Dendritic cells
SPECIFIC BINDING SITES
Between antigenic site gp120 of the virus and CD4 receptor
o T helper lymphocyte
o Monocyte
o Lymphocyte
o Dendritic cells
**Gp120 must also bind to other cell surface molecules (coreceptors: chemokine receptors) for cell entry
o CCR5
o CXCR4
ACUTE IMMUNODEFICIENCY SYNDROME - Pathogenesis
ACUTE IMMUNODEFICIENCY SYNDROME - Pathogenesis
Sequence of events as HIV enters the cell
Evidences demonstrating the importance of HIV binding to co-receptors:
o Engineered non-lymphoid cells for CD4 without co-receptors cannot be infected with HIV
o Chemokines sterically hinder HIV infection of cells in culture by occupying their receptors.
o Mutation of CCR5 renders individuals resistant to HIV infection (homozygotes)
ACUTE IMMUNODEFICIENCY SYNDROME - Life Cycle of HIV
The life cycle of HIV consists of:
o Infection of cells
o Integration of the provirus into the host cell genome
o Activation of viral replication
o Production and release of infectious virus
ACUTE IMMUNODEFICIENCY SYNDROME - Life Cycle of HIV
Life Cycle of HIV. HIV gp 120 envelope glycoprotein binds to CD4 receptor => Conformational change: Formation of new recognition site on gp120 for coreceptors CCR5 and CXCR => Binding of g120 to coreceptors (CCR5and CXCR4) => Conformational change: Exposure of hydrophobic region (called fusion peptide) at the tip of gp41 => This peptide inserts to the cell membrane of the target cells => Fusion of virus to the host cell => Virus core containing the HIV genome enters the cytoplasm of the host cell => RNA genome undergoes reverse transcription => Synthesis of proviral DNA
There are 2 types of viruses: RNA viruses and DNA viruses. RNA viruses multiply in the cytoplasm where the RNA locus is. DNA viruses multiply in the nucleus where the DNA locus is.
HIV is an RNA virus and yet it multiplies in the nucleus. The reason for this is the presence of reverse transcriptase which reverses the sequencing of RNA. Recall that RNA is just the reverse of DNA
ACUTE IMMUNODEFICIENCY SYNDROME - Mechanism of CD4 Cell Loss in HIV
3 Mechanisms of CD4 loss:
1. From actual invasion of HIV virus
o Due to direct cytopathic effects of the replicating virus
o Productive infection of T cells and viral replication in infected cells is the major mechanism by which HIV causes lysis of CD4+ T cells
- Approximately 100 billion virus new particles are produced/day
- 1-2B CD4+ cells die/day
- Exhaustion of uninfected T-cells from cytokine release
o In the presence of the virus, there would be chronic activation of uninfected CD4+ T-cells => Release of products such as cytokines => Exhaustion occurs => Cell death via apoptosis - Killing of infected cells by virus-specific CTLs (cytotoxic T cells)
o HIV-specific CTL recognizes virus infected cell Expresses HIV peptides on these cells Killing of virus infected cells
Other mechanisms causing T-cell destruction:
o Destruction of RES cells
o Loss of immature precursors of CD4+ T-cells: Direct infection of progenitor cells and cytokines producing accessory cells needed for CD4+ cells production
o Fusion of uninfected and infected cells => virus can easily go to the uninfected cell. Note: fusion of the uninfected and infected cells causes the formation syncitia or giant cells.
HIV Infection of Non-T cells
o CD4 T cells, macrophages and follicular dendritic cells contained in the lymphoid tissues are the major sites of HIV infection and persistence
ACUTE IMMUNODEFICIENCY SYNDROME - Major Abnormalities of Immune Function in AIDS
Lymphopenia
o Predominantly due to selective loss of the CD4+ helper-inducer T-cell subset;
o Inversion of CD4:CD8 ratio (in virus infected patients CD8 levels become higher)
Decreased T-Cell Function In Vivo
o Preferential loss of memory T cells
o Susceptibility to opportunistic infections
o Susceptibility to neoplasms
o Decreased delayed-type hypersensitivity
Altered T-Cell Function In Vitro
o Decreased proliferative response to mitogens, alloantigens, and soluble antigens
o Decreased specific cytotoxicity
o Decreased helper function for pokeweed mitogen-induced B-cell immunoglobulin production
o Decreased IL-2 and TFN-γ production
Polyclonal B-Cell Activation
o Hypergammaglobulinemia and circulating immune complexes seen early in HIV infection
o Inability to mount de novo antibody response to a new antigen
o Vaccine refractoriness to the normal signals for B-cell activation in vitro
**Because of no CD40 ligand: Necessary for activation of your B cell and decreased CD4 cells that would present your antigen to B-cell.
Altered Monocyte or Macrophage Functions
o Decreased chemotaxis and phagocytosis
o Decreased HLA class II (MHC II) antigen expression
o Diminished capacity to present antigen to T cells
o Increased spontaneous secretion of IL-1, TNF, IL-6
**There are no caseous necrosis, no epitheloid cell, no granulomatous formation - due to CD4 cell destruction.
ACUTE IMMUNODEFICIENCY SYNDROME - Pathogenesis of CNS Infection
Macrophages and microglia are the predominant cell types in the brain that are infected with HIV
Infected monocytes carry HIV into the brain
Viral products and soluble factors produced by infected microglia are the culprits for the severity of the symptoms
o IL-1, TNF, and IL-6
o Nitric Acid produced by gp41
o Direct damage of neurons by soluble HIV gp 120
o Neurotoxins trigger excessive entry of Ca²+ in neurons
o Through glutamate activated ion channels
ACUTE IMMUNODEFICIENCY SYNDROME - Three Phases reflecting dynamics of virus-host interaction
- Acute retroviral syndrome (3-6 wks after infection)
o High virus level production
o Viremia
o Widespread seeding of lymphoid tissue
o Resolves spontaneously 2-4 weeks
o Non-specific symptoms: sore throat, myalgias, fever, rash, weight loss, fatigue
o Clinical features: rash, cervical adenopathy, diarrhea, vomiting - Middle chronic phase (7 to 10 years)
o Containment of the virus period of clinical latency
o Intact immune system
o Continuous HIV replication, predominantly in the lymphoid tissue, may last for several years
o Either asymptomatic/persistent generalized lymphadenopathy
o Minor opportunistic infections: thrush, herpes zoster
o Persistent lymphadenopathy with significant constitutional symptoms (fever, rash, fatigue) reflects onset of immune system decompensation, escalation of viral replication and onset of crises phase - Final: Full blown/progression to AIDS
o Breakdown of host defense, increase plasma virus and clinical disease
o Fever of more than 1 month duration, fatigue, weight loss and diarrhea.
o Serious opportunistic infections, secondary neoplasms,
ACUTE IMMUNODEFICIENCY SYNDROME - CDC Classification Categories of HIV Infection
Blood CD4+ counts is the strongest indication of disease progression
Category 1: CD4+ greater than or equal to 500 cell/μl (already a full blown case)
Category 2: 200 to 499 cells/μl
Category 3: Fewer than 200 cells/μl
ACUTE IMMUNODEFICIENCY SYNDROME - AIDS defining Opportunistic Infections and Neoplasms
Opportunistic infections account for the majority of deaths in untreated patients with AIDS.
o Many of these infections represent reactivation of latent infections, which are normally kept in check by a robust immune system but are not completely eradicated because the infectious agents have evolved to coexist with their hosts.
INFECTIONS:
1. Protozoal and Helminthic Infections
o Cryptosporidiosis
o Pneumocystis (pneumonia or disseminated infection)
o Toxoplasmosis (pneumonia or CNS infection)
2. Fungal Infections
o Candidiasis (esophageal, tracheal, pulmonary)
o Cryptococcosis (CNS Infection)
o Coccidioidomycosis (disseminated)
o Histoplasmosis (disseminated)
3. Bacterial Infections
o Mycobacteriosis (atypical, e.g. M. avium intracellulare, disseminated or extrapulmonary; M. tuberculosis, pulmonary or extrapulmonary)
o Nocardiosis (pneumonia, meningitis, disseminated)
o Salmonella infections, disseminated
4. Viral Infections
o Cytomegalovirus (pulmonary, intestinal, retinitis, CNS)
o Herpes simplex virus (localized or disseminated)
o Varicella-zoster virus (localized or disseminated)
o Progressive Multifocal leukoencephalopathy
ACUTE IMMUNODEFICIENCY SYNDROME - AIDS defining Opportunistic Infections and Neoplasms
Neoplasms
o Patients with AIDS have a high incidence of certain tumors.
Commonality: caused by oncogenic DNA viruses
- Kaposi Sarcoma
- B Cell Non-Hodgkin Lymphoma
- Primary Lymphoma of the Brain
- Invasive Cancer of the Uterine Cervix
ACUTE IMMUNODEFICIENCY SYNDROME - Neoplasms
Kaposi Sarcoma
o Patients with KS herpes virus (KSHV) or human herpes virus 8 serotype will only be the ones who will have Kaposi sarcoma
o Vascular tumor; most common neoplasm in patients with AIDS
o Composed of mesenchymal cells and proliferation of these cells are driven by cytokines and growth factors that are derived from tumor cells and HIV- infected cells
o Characterized by spindle shaped cells that express markers of both endothelial (vascular of lymphatic) and smooth muscle cells
o Profusion of slit like vascular spaces, suggesting that lesion arises from mesenchymal precursors
**
Q: Patients with Kaposis Sarcoma are noted to be?
A: (+) for antibody HHV8
ACUTE IMMUNODEFICIENCY SYNDROME - Neoplasms
B Cell Non-Hodgkin Lymphoma
o B cell Non-Hodgkin’s Lymphoma is the most common type of lymphoma in AIDS patient
o Vast majority of AIDS-associated lymphoma
o Pathogenesis: sustained polyclonal B-cell activation, followed by the emergence of monoclonal or oligoclonal B-cell populations
Histologic features of Non-Hodgkin lymphoma
ACUTE IMMUNODEFICIENCY SYNDROME - Neoplasms
Primary Lymphoma of the Brain
o Noted in 20% of HIV infected patients who develop lymphomas
o 1000 times more common in patients with AIDS than the general population
o Half of the systemic B cell lymphomas and virtually all lymphomas primarly in the central nervous system are latently infected with Epstein-Barr virus (EBV)
ACUTE IMMUNODEFICIENCY SYNDROME - Neoplasms
Invasive Cancer of the Uterine Cervix
o Related to Human Papilloma Virus infection
o Characterized by spindle shaped cells that express markers of both endothelial (vascular of lymphatic) and smooth muscle cells
o Profusion of slit like vascular spaces, suggesting that lesion arises from mesenchymal precursors
