1. Just like we said “EVERY disease is a genetic disease”, we can also say “EVERY disease is an ‘immune’ disease.”
Diseases of IMMUNITY

2. OBJECTIVES
Differentiate between the concepts of “Innate” and “Adaptive” immunity
Visually recognize and understand the basic roles of lymphocytes, macrophages, dendritic cells, NK cells in the immune saga
Understand the roles of the major cytokines in immunity
Differentiate and give examples of the four (4) different types of hypersensitivity reactions: Allerg, Auto-Ab, Ag/Ab, DH

3. OBJECTIVES
Know the common features of autoimmune diseases, and the usual four (4) main features (Etiology, Pathogenesis, Morphology, and Clinical Expression) of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Sjögrens, Systemic Sclerosis (Scleroderma), Mixed Connective Tissue Disease, and “Poly-” (aka, “Peri-”) -arteritis Nodosa
Differentiate between Primary (Genetic) and Secondary (Acquired) Immunodeficiencies

4. OBJECTIVES
Understand the usual four (4) main features of AIDS, i.e., etiology, pathogenesis, morphology, clinical expression
Understand the usual four (4) main features of Amyloidosis

5. IMMUNITY INNATE (present before birth, “NATURAL”)
ADAPTIVE (developed by exposure to pathogens, or in a broader sense, antigens not recognized by the MHC)
Unlearned vs. Learned
Diploma vs. street experience
Having a weapon, knowing when and how to use it.

6. THE INNATE IMMUNE SYSTEM: MECHANISMS OF INNATE IMMUNITY Healthy individuals are able to resist potentially harmful microorganisms in the environment by a number of very effective mechanisms present from birth. These mechanisms do not depend on previous experience of any particular microorganism. The innate immune mechanisms are non-specific in the sense that they are effective against a wide range of potentially harmful pathogens. microorganism..

7. Determinants of Innate Immunity The main determinants of innate immunity are genetically controlled, varying widely between species and strains; and to a lesser extent between individuals. Age, sex and hormones also play little roles The determinants of innate immunity can be categorized into three (3): 1. Species and strain 2. Individual differences and influence of age. 3. Nutritional factors and hormonal influences.

8. Mechanical and Physiological Barriers / Bactericidal Substances The exterior of the body presents an effective barrier to most organisms; in particular most infectious agents cannot penetrate intact skin. The importance of this barrier is made abundantly clear when an individual suffers serious burns. In this case, prevention of infection via the damaged skin is a major concern. Most infections enter the body via the epithelial surface of the nasopharynx, gut, lungs and genito-urinary tract. A variety of physical and biochemical defenses protect these areas from most infections.

9. For example, the damp surface of the mucous membranes of the respiratory tract acts as a trapping mechanism and together with the action of the cilia, sweep away foreign particles so that it passes into the saliva and is swallowed. Mucus of the GIT can trap organisms and the effect of peristalsis prevents bacteria overgrowth. On reaching the stomach, the acid gastric secretions get rid of any microorganism present. Nasal secretions and saliva contains mucopolysaccharides capable of inactivating some viruses; and the tears contain Lysozyme which is active against gram positive bacteria.

10. Lysozyme is an enzyme found in many secretions and is capable of splitting a bond found in cell wall of many bacteria. Phagocytes If any organism penetrates the epithelial surface, it encounters phagocytic cells of the RES. These cells are of several different types but they are all derived from the bone marrow stem cells. Their function is to engulf particles including infectious agents; internalize them and destroy them.

11. For this purpose they are strategically placed at where they will encounter such particles. E.g. the kupffer cells of the liver line, the sinusoids along which blood flows, and the synovial cell lines of the synovial cavity. The blood phagocytes include two major cell types: the neutrophil polymorph and the blood monocytes. Both of these cells can migrate out of the blood vessels into the tissues in response to a suitable stimulus; but they differ in that, the polymorph (also known as microphage) is short-lived while the monocyte develops into a tissue macrophage.

12. NK Cells and Soluble Factors The natural killer (NK) cells are non-phagocytic lymphoid cells that are readily detectable in the circulation and in the spleen of man. They are devoid of conventional surface markers of other lymphoid cells of the specific immune system. The number of these cells in the circulation decline with age. NK cells are leucocytes capable of recognizing cell surface changes on virally-infected cells.

13. The NK cells bind to these target cells and can kill them
The NK cells bind to these target cells and can kill them. The NK cells are activated by interferons (a family of glycoproteins) which are themselves components of the innate immune system. Interferons are produced (within a few hours) by virally-infected cells and sometimes also by lymphocytes. Apart from their action on NK cells, interferons induce a state of viral resistance in neighbouring uninfected tissue cells through special receptors on the cells, without interfering with their normal metabolic processes.

14. INNATE IMMUNITY BARRIERS
CELLS: LYMPHOCYTES, MACROPHAGES, PLASMA CELLS, NK CELLS
CYTOKINES/CHEMOKINES
PLASMA PROTEINS: Complement, Coagulation Factors
Toll-Like Receptors, TLR’s
Toll-like receptors (TLRs) are a class of single membrane-spanning non-catalytic receptors on macrophages and other APCs that recognize structurally conserved molecules derived from microbes once they have breached physical barriers such as the skin or intestinal tract mucosa, and activate immune cell responses. They are very WELCOME evolutionary leftovers. You might say they are “learned” only in the evolutionary sense.
TLR’s do not arise from previous exposure to pathogenic antigens, you are born with them.

15. THE ADAPTIVE IMMUNE SYSTEM The innate immune system (the non-specific resistance) is inadequate at times (as is revealed in persons with defective immune systems; they have increased susceptibility to disease especially infectious disease). Thus the adaptive immune system is set in motion. The adaptive immune system has a dual nature:- i.e. it deals with the antigen in one of two ways; 1. The humoral response, which involves antibodies; and

16. 2. The cell-mediated response which involves intact lymphocytes
2. The cell-mediated response which involves intact lymphocytes. Upon entrance of the foreign antigenic substance into the body, the immune system ‘recognizes’ the foreign substance as not being ‘self’, processes the substance, and generally produces antibodies (in the case of humoral immune response) and/or sensitized lymphocytes (in case of cell-mediated immune response) that subsequently interact specifically with it. About a week is required after the first contact for the immune system to deal effectively with the substance in terms of being able to neutralize, destroy, or remove it.

17. Fundamental Features of the Immune Response The adaptive immune response is characterized by memory, specificity and the recognition of ‘self’ from ‘non-self’. Memory Protection or exemption from second attacks of certain diseases (e.g. measles, mumps, chicken pox, whooping cough, etc.) has been observed since ancient times. This exemption becomes possible because the first contact with an infectious organism clearly imprints some information and imparts some memory (i.e. remembers that particular infectious agent) so that the body is effectively prepared to fight or defend itself against any further invasion by the same infectious agents.

18. The antibody or sensitized lymphocyte which is produced then combines with the antigen leading to the elimination of the antigen from the system. Antibody production resulting from the first exposure to antigen is called a primary response. This differs remarkably from that seen on subsequent exposures. Following a primary injection with an antigen such as sheep red blood cells injected into a rat, there is an initial lag phase when no antibody can be detected. This is followed by phases in which the antibody rises logarithmically to a plateau and finally declines again as the antibodies are naturally catabolized or bind to the antigen and are cleared from the circulation.

19. A second exposure to the same antigen usually produces a dramatic rise in antibody level. The antibody production resulting from this second exposure is referred to as secondary response and is frequently called a specific anamnestic response, from the Greek term anamnesis, meaning ‘recall (remember)’. The antibody levels associated with this specific anamnestic response, occur with little or no lag period, and remain for long periods. The primary and secondary responses are characteristic of memory.

20. Vaccination utilizes the principle of memory by the injection of the avirulent form of the antigen (e.g. killed virus) into an animal to serve as a stimulus to print memory. The body’s immune system therefore becomes alert and any subsequent exposure to the virulent form of the same organism leads to an almost immediate production of antibody, the peak levels being hundred fold greater than primary response. This will usually prevent the infection from being established.

21. ADAPTIVE IMMUNITY
CELLULAR, i.e., direct cellular reactions to antigens
HUMORAL, i.e., antibodies
Adaptive immunity is “learned”. It relies on PREVIOUS EXPOSURE to the pathogen or foreign antigen, or even native antigen at times.

22. The classic types of adaptive immunity are:
Humoral, largely learned
Cellular, direct contact, no need for circulating antibodies

23. CELLULAR PLAYERS of the IMMUNE SYSTEM
LYMPHOCYTES, T
LYMPHOCYTES, B
PLASMA CELLS (MODIFIED B CELLS)
MACROPHAGES, aka “HISTIOCYTES”, (APCs, i.e., Antigen Presenting Cells)
“DENDRITIC” CELLS (APCs, i.e., Antigen Presenting Cells)
NK (NATURAL KILLER) CELLS
If you wanted to make this simple you can say there are 3 types of cells, T-lymphocytes, B-lymphocytes, and Macrophages or APC’s.
If you wanted to make it incredibly simple then just say lymphocytes and macrophages, i.e., the “monos” we saw in chronic inflammation, because dendritic cells have macrophage roots and functions, and plasma cells and NK cells have lymphocyte roots.

24. L Y M P H S
The many faces of a lymphocyte, NONE of which we will be seeing in histopathology lab.

25. …UNTIL PROVEN OTHERWISE
ANY ROUND CELL WITH RATHER DENSE STAINING NUCLEUS AND MINIMAL CYTOPLASM IN CONNECTIVE TISSUE, A BIT BIGGER THAN AN RBC, IS A
LYMPHOCYTE
…UNTIL PROVEN OTHERWISE
About ½ trillion lymphocytes in the human body, or 1% of all cells.

26. MACROPHAGE aka HISTIOCYTE
Even though some classify “dendritic” cells as being separate from “macrophages” you can imagine that the function of all APC’s (Antigen Presenting Cells” is to maximize surface area.
Of all the names for this type of cell, macrophage, histiocyte, Kupffer cell, Reticuloendothelial cell, dendritic cell, monocyte, the name I like best is APC, or Antigen Presenting Cell, because it tells what the cell DOES too!

27. Even though we call a macropahge a “mono”-cyte, conventionally, it’s nucleus can be as convoluted or “cerebrated” as a neutrophil.
Are almost all “pigmented” cells in the body, intrinsic or extrinsic, macrophages? Yes!
Most cells that are dispersed throughout tissues, and have a single nucleus and GRANULES, are macrophages!
Pathologists love to call macrophages “histiocytes”, historically.
MACROPHAGES are MONOCYTES that have come out of circulation and have gone into tissue

28. MACROPHAGES It is very important to understand the “misnomer”.
We called neutrophils “polys” because of “poly” or “multi” lobes in its nucleus.
And we called lymphs and macrophages “monos” because we said the nuclei were “mono”nucleaded.
But in reality, the nucleus of a macrophage (aka, tissue monocyte) can be VERY convoluted, or “cerebrated”.

29. …UNTIL PROVEN OTHERWISE
ANY CELL MIXED IN WITH LYMPHOCYTES BUT HAS A LARGER MORE “OPEN”, i.e., “vesicular”, LESS DENSE, LESS CIRCULAR NUCLEUS WITH MORE CYTOPLASM IS A
MACROPHAGE
…UNTIL PROVEN OTHERWISE
ALMOST ALL “GRANULAR” or “PIGMENTED” CELLS IN CONNECTIVE TISSUE ARE MACROPHAGES. GRANULOMAS, GIANT CELLS, ARE CHIEFLY MACROPHAGES ALSO.
It might also be allowed to call a macrophage a “APC”, i.e., an Antigen Presenting Cell, of cellular immunity.

30. PLASMA CELLS 1) ROUND NUCLEUS 2) OVOID CYTOPLASM
3) PERIPHERAL CHROMATIN
4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF CYTOPLASM
Plasma are B-lymphocytes that have dedicated themselves to be antibody factories, stuffing their golgi apparatus with immunoglobulins.
If you see a cell with these 4 features, it can only be a plasma cell, even if it has, say 2-3 features, it still may very well be a plasma cell!
PLASMA CELLS

31. A Dendridic cell is a type of macrophage (i. e
A Dendridic cell is a type of macrophage (i.e., APC) with many spiny cytoplasmic processes, found in many places especially skin (Langhans cells) and brain (microglia), and many other less known places like liver. They are also APC’s. They are found in many many places however.
Can you call dendritic cells “max” macs? I think so, because they maximize their surface area.

32. NK CELLS
NK cells are types of lymphocytes which specialize in direct killing of cells which the come in contact with, hence the term NK, Natural Killer.
Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses. The cells kill by releasing small cytoplasmic granules of proteins called PERFORIN and GRANZYME that cause the target cell to die by apoptosis. The cell reminds me of the Rodney Dangerfield’s joke where he says his football team was so tough, after they sacked the quarterback, they then went after his family.
NK cells do not “phagocytize”, they just Kill, Naturally.

33. NK cells are lymphocytes which specialize in direct killing of cells which the come in contact with, hence the term NK, Natural Killer.
Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system.
NK cells play a major role in the rejection of tumors and cells infected by viruses.
The cells kill by small  cytoplasmic granules of proteins PERFORIN and GRANZYME that cause the target cell to die by apoptosis.

34. The funniest crossword puzzle clue in history
The funniest crossword puzzle clue in history! “What is the very last word you will say to a sentry?” “FOE”
The NK cell is a crucial gatekeeper or sentry of the MHC. Halt, who goes there? Friend or foe?
An NK cell is activated or not, whether it recognizes a MHC I cell or not.
So what kills the virus infected cell, the virus or the NK cell? They BOTH may!
Would you call a cell which has to have its inhibitory recepter activated just to not kill its friends, an aggressive cell? Hell, yes!

35. GENERAL SCHEME of CELLULAR EVENTS
APCs (Macrophages, Dendritic Cells)
T-Cells (Control Everything)
CD4 “REGULATORS” (Helper)
CD8 “EFFECTORS”
B-Cells Plasma Cells AB’s
NK Cells
What kind of lymphocyte do you think is more important, a strategist general (CD4) or a soldier (CD8)?
Do you think B-Cells might have evolved in time from T-cells, by virtue of its capacity to kill without even making contact, e.g., rifle vs. club?

36. General roles of B and T cells. Which cell is most akin to a NK cell
General roles of B and T cells. Which cell is most akin to a NK cell? ANS: CD8, aka, cytotoxic T-lymphocyte.

37. CYTOKINES MEDIATE INNATE (NATURAL) IMMUNITY, IL-1, TNF, INTERFERONS
REGULATE LYMPHOCYTE GROWTH (many interleukins, ILs)
ACTIVATE INFLAMMATORY CELLS
STIMULATE HEMATOPOESIS, (CSFs, or Colony Stimulating Factors)
Just as EPO is to red cells, CSF is to granulocytes and macrophages

38. CYTOKINES/CHEMOKINES
CYTOKINES are PROTEINS produced by MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation, AND immunity
TNF, IL-1, by macrophages
CHEMOKINES are small proteins which are attractants for PMNs
This is the same EXACT slide from our discussion of acute inflammation.

39. MHC Major Histocompatibility Complex
A genetic “LOCUS” on Chromosome 6, short arm, which codes for cell surface compatibility
Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice
It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized antigens will NOT be tolerated

40. 6p21.3
Top->Centromere
I, III, II

41. MHC MOLECULES (Gene Products)
I (All nucleated cells and platelets), cell surface glycoproteins, ANTIGENS
II (APC’s, i.e., macs and dendritics, lymphs), cell surface glycoproteins, ANTIGENS
III Complement System Proteins
Why these 3?
I) Present II) Recognize III) Attack

42. IMMUNE SYSTEM DISORDERS WHAT CAN GO WRONG?
HYPERSENSITIVITY REACTIONS
“AUTO”-IMMUNE DISEASES, aka “COLLAGEN” DISEASES (BAD TERM) Inflammation NOT due to external pathogens, MHC failure.
IMMUNE DEFICIENCY SYNDROMES, IDS:
PRIMARY (GENETIC)
SECONDARY (ACQUIRED)
This is the outline of our entire chapter 6.
Why were autoimmune diseases called “collagen” diseases? Because fibrosis often follows chronic inflammation, and the MAIN pattern of autoimmune diseases is CHRONIC inflammation, NOT usually acute, i.e., many systemic autoimmune diseases eventually evoke fibrosis.

43. HYPERSENSITIVITY REACTIONS (4)
I (Immediate Hypersensitivity)
II (Antibody Mediated Hypersensitivity)
III (Immune-Complex Mediated Hypersensitivity)
IV (Cell-Mediated Hypersensitivity)
A good understanding of the 4 different types of classical “hypersensitivity” reactions, should be obtained. These are always taught as the general FOUR types of hypersensitivity, but are by no means complete or mutually exclusive. These 4 items have ALWAYS been taught this way, even if more recent knowledge implies it is ridiculous to classify them this way.

44. Type I IMMEDIATE HYPERSENSITIVITY
“Immediate” means seconds to minutes
“Immediate Allergic Reactions”, which may lead to anaphylaxis, shock, edema, dyspnea death
1) Allergen exposure
2) IMMEDIATE phase: MAST cell DEgranulation, vasodilatation, vascular leakage, smooth muscle (broncho)-spasm
3) LATE phase (hours, days): Eosinophils, PMNs, T-Cells
The MAST cell is the key cell if Type I Hypersensitivity.
What are the granules in mast cells composed of? HHS

45. TYPE II HYPERSENSITIVITY ANTIBODY MEDIATED IMMUNITY
ABs attach to cell surfaces
OPSONIZATION (basting the turkey)
PHAGOCYTOSIS
COMPLEMENT FIXATION (cascade of C1q, C1r, C1s, C2, C3, C4, C5….. )
LYSIS (destruction of cells by rupturing or breaking of the cell membrane)
Attacking cell or microbial membranes is the key feature of Type II Hypersensitivity.
Complement cascades are needed for LYSIS of cells, NOT just antibody attachment.

46. TYPE II DISEASES Autoimmune Hemolytic Anemia, AHA
Idiopathic Thrombocytopenic Purpura, ITP
Goodpasture Syndrome (Nephritis and Lung hemorrhage)
Rheumatic Fever
Myasthenia Gravis
Graves Disease
Pernicious Anemia, PA
Understandably, these are all “AUTO”-immune diseases, or FAILURES of the MHC. Note most are organ-specific (i.e., “local”) rather than systemic.
But beware, many autoimmune diseases which have an organ’s name in them may very well be SYSTEMIC, like RA, SjS, DMS

47. TYPE III HYPERSENSITIVITY IMMUNE COMPLEX MEDIATED
Antigen/Antibody “Complexes”
Where do they go?
Kidney (Glomerular Basement Membrane)
Blood Vessels
Skin
Joints (synovium)
Common Type III Diseases- SLE (Lupus), Poly(Peri)arteritis Nodosa, Poststreptococcal Glomerulonephritis, Arthus reaction (hrs), Serum sickness (days)
An Arthus reaction is a local vasculitis associated with deposition of immune complexes and activation of complement. Immune complexes form in the setting of high local concentration of vaccine antigens and high circulating antibody concentration. Arthus reactions are characterized by severe pain, swelling, induration, edema, hemorrhage, and occasionally by necrosis. These symptoms and signs usually occur 4–12 hours after vaccination.
Serum sickness symptoms can take as long as fourteen days after exposure to appear, and may include signs and symptoms commonly associated with allergic reactions or infections, such as rashes, itching, joint pain (arthralgia), fever, and swollen lymph nodes (lymphadenopathy), and malaise. Historically, it was a result of animal serum injections.
Think of GBM, Blood Vessels, SKIN, and SYNOVIUM as all being MAGNETS for Ag/Ab complexes. “Just when I thought I was out, they pull me back in!”

48. TYPE IV HYPERSENSITIVITY CELL-MEDIATED (T-CELL) DELAYED HYPERSENSITIVITY
Tuberculin Skin Reaction
DIRECT ANTIGENCELL CONTACT
GRANULOMA FORMATION
CONTACT DERMATITIS
No antibodies involved, as in II and III

49. SUMMARY I Acute allergic reaction
II Antibodies directed against cell surfaces
III Immune complexes
IV Delayed Hypersensitivity, e.g., Tb skin test

50. RENAL TRANSPLANT REJECTION
HYPERACUTE (minutes) : AG/AB reaction of vascular endothelium
ACUTE (days months): cellular (INTERSTITIAL infiltrate, possibly “monos”) and humoral (VASCULITIS)
CHRONIC (months): slow vascular fibrosis
Clinical vs. pathological, acute and chronic.

51. AUTO-IMMUNE DISEASES TOLERANCE (Success of MHC)
Failure of SELF RECOGNITION
Failure of SELF TOLERANCE
TOLERANCE (Success of MHC)
CENTRAL (BEFORE lymph maturation) (Death of self reactive lymphocytes)
PERIPHERAL (AFTER lymph maturation) (pregnancy, anergy, suppression by regulatory CD4 T-cells, deletion by apoptosis, sequestration (Ag masking))
STRONG GENETIC PREDISPOSITION
OFTEN RELATED TO OTHER AUTOIMMUNE DISEASES
OFTEN TRIGGERED BY INFECTIONS
Central tolerance occurs DURING lymphocyte development and operates in the thymus and bone marrow. Here, T and B lymphocytes that recognize self antigens are deleted before they develop into fully immunocompetent cells, preventing autoimmunity.
Peripheral tolerance  is immunological tolerance developed AFTER T and B cells mature and enter the periphery.
Acquired or induced tolerance refers to the immune system's adaptation to external antigens characterized by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would likely induce cell-mediated or humoral immunity. One of the most important natural kinds of acquired tolerance is immune tolerance in pregnancy, where the fetus and the placenta must be tolerated by the maternal immune system.
Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance.

52. CLASSIC AUTOIMMUNE DISEASES (SYSTEMIC)
LUPUS (SLE) Systemic Lupus Erythematosus
RHEUMATOID ARTHRITIS
SJÖGREN SYNDROME
SYSTEMIC SCLEROSIS (scleroderma)
MCD (Mixed Connective Tissue Dis.)
Poly (Peri-) arteritis nodosa
Please do not think that because the names of some of these SYSTEMIC auto-immune diseases seem to localize to certain areas, like joints, salivary glands, or skin, that they are NOT SYSTEMIC diseases.
Many/most of these may have some kind of ANA positivity.

53. CLASSIC AUTOIMMUNE DISEASES (LOCAL)
HASHIMOTO THYROIDITIS
AUTOIMMUNE HEMOLYTIC ANEMIA
MULTIPLE SCLEROSIS
AUTOIMMUNE ORCHITIS
GOODPASTURE SYNDROME
AUTOIMMUNE THROMBOCYTOPENIA (ITP)
“PERNICIOUS” ANEMIA
INSULIN DEPENDENT DIABETES MELLITUS
MYASTHENIA GRAVIS
GRAVES DISEASE
It is always dangerous to call a disease “local” because the more we study it, the more we realize it isn’t.
Nevertheless, this is the classic list of “local” autoimmune diseases.

54. N.B.
The list of diseases proven to be “autoimmune” grows by leaps and bounds every year!!!
Would it be fair to say EVERY disease is autoimmune? Probably NOT!
Would it be fair to say almost every disease can result as a failure of some immune process? Probably!
Would it fair to say inflammatory diseases can be divided into pathogen-caused and autoimmune? Perhaps.

55. LUPUS (SLE)
Etiology: Antibodies (ABs) directed against the patient’s own DNA, HISTONES, NON-histone RNA, and NUCLEOLUS
Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS
Morphology: “Butterfly” rash (NOT discoid)
, skin deposits, glomerolunephritis
Clinical expression: Progressive renal and vascular disease
CCPP*** declining renal function in a younger woman, e.g.

57. H O M S P E C K R I M N U C L E O A
Please note that there are 4 classical patterns of ANA, and there is a clinical difference between these patterns, but there is so much overlap, it is probably not worth going into this deeper.
Homo: MANY autoimmune diseases, anti-DNA antibody
Speckled: Sjogrens, Scleroderma, MCD
RIM: anti-ds(double stranded) DNA, MOST CLASSIC FOR SLE
Nucleolar: Scleroderma, Polymyositis

58. Prevalence in Patients, %
TABLE Clinical and Pathologic Manifestations of Systemic Lupus Erythematosus
Clinical Manifestation
Prevalence in Patients, %
Hematologic
100
Arthritis
90 
Skin
85 
Fever
83 
Fatigue
81 
Weight loss
63 
Renal
50 
Central nervous system
Pleuritis
46 
Myalgia
33 
Pericarditis
25 
Gastrointestinal
21 
Raynaud phenomenon
20 
Ocular
15 
Peripheral neuropathy 14
Renal failure in a young woman is always highly suspect of lupus.
Does it look like there is any major body system which lupus ignores? Answer: NO

59. MORE SYSTEMIC AUTOIMMUNE DISEASES
RHEUMATOID ARTHRITIS
SJÖGREN SYNDROME
SCLERODERMA (SYSTEMIC SCLEROSIS)

60. Rheumatoid Arthritis
Rheumatoid factor (RF or RhF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of IgG, which is itself also an antibody.
In rheumatoid arthritis the primary areas of the body ravaged by autoimmune destruction are synovium and blood vessels.

61. ANTIBODY AGAINST Fc PORTION OF IgG
Rheumatoid factor (RF or RhF) is an autoantibody (antibody directed against an organism's own tissues) most relevant in rheumatoid arthritis. It is an antibody against the Fc portion of IgG, which is itself also an antibody.
In rheumatoid arthritis the primary areas of the body ravaged by autoimmune destruction are synovium and blood vessels.

62. MORE AUTOIMMUNE DISEASES (LOCAL)
HASHIMOTO THYROIDITIS (anti-thyroglob, anti-microsome)
AUTOIMMUNE HEMOLYTIC ANEMIA (AHA) (anti-RBC)
MULTIPLE SCLEROSIS (anti-MBP)
AUTOIMMUNE ORCHITIS (Anti-germ cell)
GOODPASTURE SYNDROME (anti-GBM Ab’s)
AUTOIMMUNE THROMBOCYTOPENIA (ITP) (anti-plats)
“PERNICIOUS” ANEMIA (anti-IF, anti-parietal cell Ab’s)
INSULIN DEPENDENT DIABETES MELLITUS (I) (anti-islets)
MYASTHENIA GRAVIS (anti-NM-junction)
GRAVES DISEASE (anti-TSHR-Ab’s cause activation)
I think you should, as a knee jerk reflex, ALWAYS know, if you hearese diseases mentioned, that they are ALL autoimmune diseases, but rather localized rather than systemic.
Don’t you find it interesting that the most common causes of adult hypo- and hyper- thyroidism are BOTH autoimmune diseases?

63. ImmunoDefiency Syndromes (-IDS)
PRIMARY (GENETIC) (P-IDS?)
SECONDARY (ACQUIRED) (A-IDS)

64. PRIMARY
CHILDREN with repeated, often severe infections, cellular AND/OR humoral immunity problems, autoimmune defects
BRUTON (X-linked agammaglobulinemia)
COMMON VARIABLE
IgA deficiency
Hyper -IgM
DI GEORGE (THYMIC HYPOPLASIA) *22q11.2
SCID (Severe Combined Immuno Deficiency)
….with thrombocytopenia and eczema (WISKOTT-ALDRICH)
COMPLEMENT DEFICIENCIES
22q11.2 deletion syndrome, also known as Velocardiofacial Syndrome, DiGeorge Syndrome and Strong Syndrome is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2. It has a prevalence estimated at 1:4000. Do you remember what CATCH is the mnemonic for? Hint: the “T” stands for “T”hymic aplasia.
SCID: Chronic diarrhea, ear infections, recurrent Pneumocystis jirovecii pneumonia, and profuse oral candidiasis commonly occur. These babies, if untreated, usually die within 1 year due to severe, recurrent infections. However, treatment options are much improved since David Vetter, “the Boy in the Bubble”.
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954.
You should probably know the clinical presentation “profiles” of these patients with PIDS (PRIMARY Immune Deficiency Syndromes)
Bruton’s: Males (of course) with infections, especially enteroviral, after a few months of life, after maternal antibodies are gone.
COMMON VARIABLE: Most patients in 20’s, UTIs, LTIs
IgA Deficiency: Usually NO symptoms
Hyper IgM: Recurrent pyogenic infections, pneumonia, PCP, neutropenia, thrombocytopenia.
DiGeorge: Birth defects, learning disabilities, infections, thymus problems. *C-A-T-C-H:
Cardiac Abnormality (especially Fallot's Tetralogy) Abnormal facies Thymic aplasia Cleft palate Hypocalcemia
SCID: Candidiasis, diaper rash, failure to thrive, “The Boy in the Bubble”

65. Examples of Infections in Immunodeficiencies
Pathogen Type
T-Cell-Defect
B-Cell Defect
Granulocyte Defect
Complement Defect
Bacteria
Bacterial sepsis
Streptococci, staphylococci, Haemophilus
Staph, Pseudomonas
Neisserial infections, other pyogenic infections
Viruses
Cytomegalovirus, Epstein-Barr virus, severe varicella, chronic infections with respiratory and intestinal viruses
Enteroviral encephalitis
Fungi and parasites
Candida, Pneumocystis carinii
Severe intestinal giardiasis
Candida, Nocardia, Aspergillus
Special features
Aggressive disease with opportunistic pathogens, failure to clear infections
Recurrent sinopulmonary infections, sepsis, chronic meningitis
This is a useful slide for understanding, VERY GENERALLY, which kinds of infections result from which kinds of deficiencies. As you can see, there is considerable overlap. Bear with me on this one, please.
Note that the RED pathogens are fairly typical for defects in the class of defects ABOVE them
Why are the T-Cell defect diseases not surprising???

66. (A)IDS(SECONDARY IDS)
Etiology: HIV
Pathogenesis: Infection, Latency, Progressive T-Cell loss
Morphology: MANY
Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load)
Would it make sense that as the “viral load” (i.e., HIV-RNA) goes UP, the the CD4 count goes down? Ans: YES

67. EPIDEMIOLOGY HOMOSEXUAL (40%, and declining)
INTRAVENOUS DRUG USAGE (25%)
HETEROSEXUAL SEX (10% and rising)

68. ETIOLOGY
Three levels of therpeutic rationale: WHY is it NOT surprising that there are NINE things labeled here?
Block surface attachment
Anti-RT
Anti-Protease
Would it also make sense that an antibody to an EXTERNAL antigen become positive BEFORE an antibody to an INTERNAL (i.e., “core”) antigen?

69. REVERSE TRANSCRIPTASE
The enzyme reverse transcriptase (RT) is used by retroviruses to transcribe their single-stranded RNA genome into single-stranded DNA and to subsequently construct a complementary strand of DNA, providing a DNA double helix capable of integration into host cell chromosomes.
Hoping to understand the process of “reverse” transcription RNADNA.
Reverse transcriptase creates single stranded DNA from a RNA template.

70. This is NOT intended for memorization
This is NOT intended for memorization. Just understand the gene/gene-product scheme of things.
How many genes does HIV have? Only 9 !!!!! Humans: 24,000
PATHOGENESIS

71. PATHOGENESIS 1) PRIMARY INFECTION 2) LYMPHOID INFECTION
3) ACUTE SYNDROME 4-8 weeks)
4) IMMUNE RESPONSE
5) LATENCY
6) AIDS
What about the patient?
AIDS , rather than HIV infection, is characterized by multiple opportunistic infections.
Where in this spectrum would the “HIV” (i.e. antibody) test be positive?
When would the viral load (RNA) be the highest?
At what stage does the patient first feel the viral prodromal symptoms?
What is the average “latency” period? ~~years, often many!

72. On the left is plotted CD4 cells and viremia (viral load), on the right are various antibodies.
In general. SURFACE antibodies appear earlier than deeper core antibodies. This is true of most viral illnesses, especially hepatitis.
CTLs=Cytotoxic T Lymphocytes

73. GENERAL IMMUNE ABNORMALITIES
LYMPHOPENIA
DECREASED T-CELL FUNCTION
B-CELL ACTIVATION, POLYCLONAL
ALTERED MONOCYTE/MACROPHAGE FUNCTION

74. INFECTIONS
Protozoal/Helminthic: Cryptosporidium, PCP (Pneumocystis Carinii (really Jiroveci) Pneumonia), Toxoplasmosis
Fungal: Candida, and the usual 3
Bacterial: TB, Nocardia, Salmonella
Viral: CMV, HSV, VZ (Herpes Family), HPV
Cryptosporidium is a protozoan pathogen of the Phylum Apicomplexa and causes a diarrheal illness called cryptosporidiosis

75. CANCERS of AIDS KAPOSI SARCOMA (Herpes-8) B-CELL LYMPHOMAS
CNS LYMPHOMAS
CERVIX CANCER, SQUAMOUS CELL (HPV)