Autoimmunity

The immune system is developed in a way that avoids immune attack on normal host tissues. As T cells develop in the thymus, those with high avidity for self antigens are eliminated. Most self-proteins are present in high concentrations in the thymus in development. Likewise, in the marrow the B cells in development that demonstrate high affinity to antigens are eliminated, or they may change their receptor specificity by reactivating their Ig gene recombination mechanism. These mechanisms are known as "central" tolerance because they occur within immunologic organs.

"Peripheral" tolerance occurs when T or B cells that are mature and functional encounter self antigen in peripheral tissues are are inactivated or eliminated. In the case of T cells, peripheral tolerance comes in the "failsafe" mechanism of a two signal system to activate an immune response. Even if the T cell recognizes self-antigen, the antigen processing cells are not providing the second signal-a costimulator, to activate the T cell. This situation is known as anergy. The encounter with a self-antigen may cause the T cell to express CD152 on its surface, rather than the CD28 receptor for B7 molecules that delivers second signals.

Another mechanism of peripheral tolerance occurs when a T cell undergoes repeated activation by self-antigen. This induces the appearance of a "death receptor" called Fas and its ligand Fas-L on the cell surface. Thus, two T cells expressing these macromolecules can interact to activate cellular caspases that initiate apoptosis. Another possible mechanism is the elaboration of cytokines by suppressor T cells that have encountered self-antigens that inhibit the actions of other lymphocytes.

Peripheral B cell tolerance occurs when there are no supporting T cells, in the case of protein antigenic stimulation that is T cell dependent. B cell responses to non-protein antigens (the body has many polysaccharide, lipid, and nucleic acid antigens) that are not dependent on T cells may require a strong antigenic signal which does not typically occur with self antigens.

Autoimmune conditions in humans can often be linked to specific MHC genes. Persons who inherit certain HLA alleles are more susecptible to development of autoimmune diseases. Such alleles may not function as well as others in displaying self antigens or stimulating suppressor cells.

Infections may promote autoimmunity. The infection can generate an immune response with costimulators that push self-reactive T cells beyond the barrier of anergy. Autoimmune diseases may have an onset that follows an infection.

There may be "sequestered" antigens such as those in the eye which the immune system does not ordinarily "see". When infection or trauma releases those antigens to immune view, then T cell activation occurs. This is the mechanism for "sympathetic ophthalmia" when damage to one eye leads to immune attack on the other normal eye.

Case Presentation:

History: A 38-year-old man comes to you at a regular office visit. He has been prompted to make this appointment by his wife, who has been noticing that he seems tired and listless, and doesn't seem to be getting any jobs done around the house. He has had no surgeries other than a hernia operation 3 years prior. He has had no major illnesses, but reports three bad episodes of the "flu" in the past year which kept him from working a couple of weeks each time. He reports having lost about 10 lbs in the past year, even though he has not been on a diet. He is on no medications, but has begun taking aspirin for what he describes as "a lot of minor aches and pains". Family members on mother's side of family have had similar problems

Physical examination: His height is 172 cm and his weight is 68 kg. Vital signs are as follows: temperature 36.7 C, respirations 20, pulse 78, and blood pressure 145/90. The HEENT exam is unremarkable. Mild tender posterior cervical lymphadenopathy is noted. The heart rate is regular and no murmurs are audible. The chest is clear to auscultation and percussion. Bowel sounds are present, and the abdomen is non-tender with no masses noted. The rectal exam reveals no masses, and the stool is guaiac negative. His extremities seem cold to the touch, but there is no cyanosis. He has 1+ ankle edema. Pulses are present in all extremities. Motor strength is about 4/5 in both upper and lower extremities. The skin of the upper chest, neck, and face appears erythematous. Deep tendon reflexes are 2+ bilaterally. Neurologic examination reveals no focal deficits. He is alert and oriented.

Laboratory findings:

Sodium	140 meq/L	136 - 144
Potassium	4.5 meq/L	3.7 - 5.2
Chloride	101 meq/L	101 - 111
CO2	26 meq/L	20 - 29
Urea Nitrogen (BUN)	18 mg/dl	7 - 20
Creatinine	1.2 mg/dl	0.8 - 1.4
Glucose	110 mg/dl	64 - 128
Alk Phos	75 U/L	45 - 150
LDH	231 U/L	105 - 230
Creatine kinase	1560 U/L	20 - 200
AST	45 U/L	9 - 55
ALT	52 U/L	3 - 46
GGT	44 U/L	0 - 24
Uric Acid	4.2 mg/dl	2.7 - 6.6
Calcium	8.4 mg/dl	8.8 - 11.0
Phosphorus	2.5 mg/dl	2.4 - 4.1
Total Protein	6.4 g/dl	6.3 - 7.9
Albumin	4.5 g/dl	3.9 - 5.0
Globulin	4.0 g/dl	2.4 - 2.9
Bilirubin, total	0.4 mg/dl	0 - 1.5
Cholesterol	165 mg/dl	100 - 200

WBC count	4200/microliter	3600 - 9000
Manual differential count	50 segs, 2 bands, 36 lymphs, 8 monos, 4 eos
Hgb	12.1 g/dl	14.9 - 17.1
Hct	36.5%	44.9 - 51.1
MCV	92 fL	86 - 96
Platelets	185,000/microlter	140 - 440

Lymphocyte subsets

CD4 cells (absolute)	610	440 - 1600
CD8 cells (absolute)	680	180 - 850

Antinuclear antibody (ANA)	1:1024 with speckled pattern
Double-stranded DNA antibody	none detected
RNP antibodies	320 units	<20
Smith antibodies	none detected
SS-A	none detected
SS-B	none detected
Rheumatoid factor	60 IU/ml	0 - 40
Complement component C3	80 mg/dl	88 - 201
Complement component C4	25 mg/dl	16 - 47
SCL-70, IgG	none detected
Centromere antibody	none detected
VDRL	Positive

Quantitative Immunoglobulins

IgA	510 mg/dl	68 - 378
IgG	2950 mg/dl	768 - 1632
IgM	480 mg/dl	60 - 263

Questions for Discussion:

1. What, if anything, suggests an immunologic disease? Are there other conditions that could account for these findings?
   
   More infections than usual suggest decreased resistance to infection. Non-specific findings of any systemic disease include weight loss and malaise. Many autoimmune diseases are accompanied by persistent aches and pains in the form of arthralgias and myalgias, without a history of soft tissue injury.
   
   
2. What physical examination findings deserve attention?
   
   The lymphadenopathy is not typical for his age. In general, nodes with malignancies (metastases or lymphomas) tend to be firm and non-tender, while reactive processes (infections, immunologic conditions) are not as firm and may be tender. He has minimal muscle weakness. The edema is clearly something you would not expect to find in a previously healthy patient at this age. The cold extremities (particularly if painful) could represent Raynaud's phenomenon.
   
   
3. What laboratory tests, if any, would be helpful?
   
   A CBC will determine if he has an anemia and indicate what his WBC count is (leukopenia for some immunologic conditions, leukocytosis for infectious processes). A chemistry panel will help determine if he has renal disease (BUN and creatinine). A CK will determine if there is muscle disease. A urinalysis will indicate if there is renal disease. The standard screening test for autoimmune diseases is the ANA, but others can be ordered as a panel if indicated. Serum immunoglobulin levels can be determined.
   
   
4. What radiologic procedures, if any, would be helpful?
   
   A chest radiograph may help to determine if he has a significant pulmonary infection.
   
   
5. Based upon the findings, including the laboratory testing, what is the most likely diagnosis?
   
   The constellation of findings points to mixed connective tissue disease, a form of autoimmune disease that has features of SLE, systemic sclerosis, and polymyositis. The RNP antibodies are highly suggestive. The long-term prognosis is better than SLE because of the general lack of renal disease with MCTD.
   
   "Speckled" Pattern of Staining Seen with "Mixed Connective Tissue Disease"
   
   

Case Presentation:

History: A 9 year old child has not wanted to get out of bed for the past day because she says that it hurts to move. The child is taken to the family physician, who notes a temperature of 38.2 C. On physical examination, there are palpable small, tender subcutaneous nodules on her extremities. She also has some scattered 1 to 2 cm erythematous macules on her trunk. Auscultation of the chest reveals clear lung fields. The heart rate is regular, with no murmurs. However, there is a suggestion of a friction rub.

What additional historical finding should be sought, and what confirmatory laboratory testing should be done?

The findings suggest acute rheumatic fever. A history of a pharyngitis preceding these events by 2 to 3 weeks is typically present. The infection is gone by the time the other symptoms appear, so culture is of no value. Instead, serologic testing will determine evidence for past infection. The three serologies specific for rheumatic fever are: antistreptolysin O (ASO), anti-DNase B, and anti-hyaluronidase antibodies. In this case, the ASO titer was 260 IU/mL (normal 0 - 240 IU/mL) and two weeks later it was 610 IU/mL. The sensitivity of the ASO is about 85%. The sensitivity of ASO and anti-DNase B together is about 95% for rheumatic fever.

What is the mechanism by which this disease is produced?

An infection may produce autoimmunity when an infectous agent has peptide antigens that are very similar to self-antigens. The infection can provide costimulation for lymphocyte activation. Once activated, the T cells can direct immune responses that also target the host tissues that have the similar antigens.

In the case of some strains of beta hemolytic group A streptococcal organisms (Streptococcus pyogenes), there is a surface M protein that is antigenically similar to glycoproteins that are found in human tissues including heart and joints. The immune response generated by the streptococcal infection, typical a "strep throat" with pharyngitis, leads to signs and symptoms of rheumatic fever in about 2 to 3 weeks. Repeated bouts of rheumatic fever can lead to increasing damage to host tissues, particularly heart valves, leading to rheumatic heart disease. Some strains of group A strep are "nephritogenic" with resultant damage to glomeruli, leading to acute renal failure. The serologic evidence for group A strep infection comes in the form of the antistreptolysin O (ASO) titer, or anti-DNase B titer.

Hypercellularity of Post-Streptococcal Glomerulonephritis

What are the criteria needed for diagnosis of acute rheumatic fever?

There are classically described "Jones criteria" which include:

Major criteria: carditis, migratory polyarthritis, subcutaneous nodules, erythema marginatum, and Sydenham's chorea.

Minor criteria: fever, arthralgia, elevated acute phase proteins such as C-rective protein.

For a diagnosis, a preceding group A streptococcal infection and two major or one major and two minor criteria must be present.

Which criteria are present in this case?

The child has serologic evidence of group A streptococcal infection. There is evidence for carditis (the friction rub suggests pericarditis), subcutaneous nodules, and erythema maginatum. The joint problem could be just arthralgia, or migratory polyarthritis, probably the former. There are three major criteria.

How is this condition prevented?

Diagnosis and treatment of acute pharyngitis with group A streptococcus ("strep throat") will greatly reduce the incidence of acute rheumatic fever.

What is the prognosis of this illness?

Acute rheumatic fever is typically self-limited and requires symptomatic therapy (anti-inflammatory drugs). If serious illness occurs, it is usually due to a myocarditis. The long term consequence is rheumatic valvulitis. One or more cardiac valves may become scarred and dysfunctional.

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Case Presentation:

History: A 23 year old woman has had malaise with myalgias for several months. She has become increasingly tired. She has noted redness of sun exposed skin when she remains outdoors for more than a half hour. She has noted becoming light-headed when arising from a chair. Yesterday she fainted, but did not incur any major trauma (she was not watching a football game and not eating pretzels). A CBC shows:

Hgb	9.8 g/dL
Hct	29.2%
MCV	104 fL
Platelet ct	113,000/microliter
WBC count	3,190/microliter
WBC diff	76 segs, 2 bands, 10 lymphs, 12 monos

What does the CBC show?

Pancytopenia. The anemia is marked, and is macrocytic. The platelet count is not decreased to dangerous levels. The leukocytes are reduced, mainly the lymphocytes

What do all the findings suggest?

The findings are protean, and there are many possibilities, but the constellation of findings suggests the possibility of an autoimmune disease. An antinuclear antibody test is ordered as is positive with a high titer?

What laboratory test should be ordered to help determine the cause for her anemia?

A Coombs test (antiglobulin test) measures the presence of antibodies to RBCs. The direct antiglobulin test detects antibody that is bound to RBCs. The indirect antiglobulin test detects circulating antibody in patient serum that is directed at RBCs. In addition, the Coombs test is carried out at differect temperatures-at 37 C and at 4 C. This determines whether the binding of antibody is "warm" or "cold".

In this case, the direct and indirect antiglobulin tests were positive at 37 C. The antibody detected was of the IgG subclass, and no bound C3 was detected.

Explain the pathophysiology of this condition.

There are two major forms of autoimmune hemolytic anemias - "warm autoimmune hemolytic anemia" and "cold agglutinin disease". Warm autoimmune hemolytic anemia is caused by the production of the IgG class of autoantibodies. The circulating antibodies bind to the red cell and lead to premature destruction. The RBCs coated with the IgG antibody attach to Fc receptors on phagocytic cells, particularly in the spleen. The phagocytes "bite out" RBC membrane with the antibody, and the RBCs get smaller and deformed, leading to their removal in the spleen. So why is the anemia macrocytic? The anemia leads to an outpouring of immature RBCs-reticulocytes-that are larger than the average RBC. Thus, the hemolysis is predominantly "extravascular" because the cells are being destroyed in the spleen.

Cases of warm autoimmune hemolytic anemia can be idiopathic or can be associated with an underlying disease such as an autoimmune disease or a malignancy or use of a drug

In cold autoimmune hemolytic anemia there is binding of IgM antibodies in peripheral parts of the body. The bound IgM starts the complement cascade. This can lead to hemolysis that is intravascular. Before hemolysis occurs, however, the RBCs may return to warmer regions of the body at 37 C. When this happens, bound IgM dissociates, but C3b remains attached. The bound C3b on the RBC membrane makes the RBC susceptible to removal by phagocytes, particularly in the spleen and liver.

Causes of cold autoimmune hemolytic anemia can be idiopathic or can be associated with an underlying disease such as mycoplasma infection, infectious mononucleosis, or malignancy such as a lymphoma.